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1.
  • Bagdonaite, I., et al. (author)
  • A Strategy for O-Glycoproteomics of Enveloped Viruses-the O-Glycoproteome of Herpes Simplex Virus Type 1
  • 2015
  • In: Plos Pathogens. - : Public Library of Science (PLoS). - 1553-7366 .- 1553-7374. ; 11:4
  • Journal article (peer-reviewed)abstract
    • Glycosylation of viral envelope proteins is important for infectivity and interaction with host immunity, however, our current knowledge of the functions of glycosylation is largely limited to N-glycosylation because it is difficult to predict and identify site-specific O-glycosylation. Here, we present a novel proteome-wide discovery strategy for O-glycosylation sites on viral envelope proteins using herpes simplex virus type 1 (HSV-1) as a model. We identified 74 O-linked glycosylation sites on 8 out of the 12 HSV-1 envelope proteins. Two of the identified glycosites found in glycoprotein B were previously implicated in virus attachment to immune cells. We show that HSV-1 infection distorts the secretory pathway and that infected cells accumulate glycoproteins with truncated O-glycans, nonetheless retaining the ability to elongate most of the surface glycans. With the use of precise gene editing, we further demonstrate that elongated O-glycans are essential for HSV-1 in human HaCaT keratinocytes, where HSV-1 produced markedly lower viral titers in HaCaT with abrogated O-glycans compared to the isogenic counterpart with normal O-glycans. The roles of O-linked glycosylation for viral entry, formation, secretion, and immune recognition are poorly understood, and the O-glycoproteomics strategy presented here now opens for unbiased discovery on all enveloped viruses.
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2.
  • Mårdberg, Kristina, 1970, et al. (author)
  • Basic amino acids as modulators of an O-linked glycosylation signal of the herpes simplex virus type 1 glycoprotein gC: functional roles in viral infectivity.
  • 2004
  • In: Glycobiology. - : Oxford University Press (OUP). - 0959-6658 .- 1460-2423. ; 14:7, s. 571-81
  • Journal article (peer-reviewed)abstract
    • The herpes simplex virus type 1 (HSV-1) glycoprotein gC-1 is engaged both in viral attachment and viral immune evasion mechanisms in the infected host. Besides several N-linked glycans, gC-1 contains numerous O-linked glycans, mainly localized in two pronase-resistant clusters in the N-terminal domain of gC-1. In the present study we construct and characterize one gC-1 mutant virus, in which two basic amino acids (114K and 117R) in a putative O-glycosylation sequon were changed to alanine. We found that this modification did not modify the N-linked glycosylation but increased the content of O-linked glycans considerably. Analysis of the O-glycosylation capacity of wild-type and mutant gC-1 was performed by in vitro glycosylation assays with synthetic peptides derived from the mutant region predicted to present new O-glycosylation sites. Thus the mutant peptide region served as a better substrate for polypeptide GalNAc-transferase 2 than the wild-type peptide, resulting in increased rate and number of O-glycan attachment sites. The predicted increase in O-linked glycosylation resulted in two modifications of the biological properties of mutant virus-that is, an impaired binding to cells expressing chondroitin sulfate but not heparan sulfate on the cell surface and a significantly reduced plaque size in cultured cells. The results suggested that basic amino acids present within O-glycosylation signals may down-regulate the amount of O-linked glycans attached to a protein and that substitution of such amino acid residues may have functional consequences for a viral glycoprotein involving virus attachment to permissive cells as well as viral cell-to-cell spread.
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3.
  • Nordén, Rickard, 1977, et al. (author)
  • Activation of host antiviral RNA-sensing factors necessary for herpes simplex virus type 1-activated transcription of host cell fucosyltransferase genes FUT3, FUT5, and FUT6 and subsequent expression of sLex in virus-infected cells.
  • 2009
  • In: Glycobiology. - : Oxford University Press (OUP). - 1460-2423 .- 0959-6658. ; 19:7, s. 776-88
  • Journal article (peer-reviewed)abstract
    • Herpes simplex virus type 1 (HSV-1) induces expression of a selectin receptor, the carbohydrate epitope sialyl Lewis X (sLe(x)), at the surface of infected cells. The molecular background to this phenomenon is that a viral immediate early RNA interacts with as yet unidentified host factors, eventually resulting in transcription of three dormant host fucosyltransferase genes (FUT3, FUT5, and FUT6), whose gene products are rate-limiting for synthesis of sLe(x). The aim of the present study was to define the immediate targets for the viral RNA in this process. We found that the Protein Kinase R (PKR) inhibitors 2-aminopurine (2-AP) and C16 inhibited FUT3, FUT5, and FUT6 expression as well as HSV-1-induced expression of sLe(x), indicating a primary role of PKR as a viral RNA target. The PKR-dependent activation of the FUT genes seemed neither to involve PKR effects on translation nor to involve NF-kappaB- or JNK-dependent activation. IMD-0354, known as an inhibitor of the NF-kappaB-activating factor IKK-2, induced FUT transcription via a novel IKK-2-independent mechanism, irrespective of whether the cells were virus-infected or not. Altogether, the results suggested that PKR is the primary target for HSV-1 early RNA during induction of FUT3, FUT5, and FUT6, and that the subsequent steps in the transcriptional activation of these host genes involve a hitherto unknown IMD-0354, yet IKK-2-independent, pathway.
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4.
  • Nordén, Rickard, 1977, et al. (author)
  • Involvement of viral glycoprotein gC-1 in expression of the selectin ligand sialyl-Lewis X induced after infection with herpes simplex virus type 1.
  • 2013
  • In: APMIS : acta pathologica, microbiologica, et immunologica Scandinavica. - : Wiley. - 1600-0463. ; 121:4, s. 280-289
  • Journal article (peer-reviewed)abstract
    • Several herpesviruses induce expression of the selectin receptor sialyl-Lewis X (sLe(x) ) by activating transcription of one or more of silent host FUT genes, each one encoding a fucosyltransferase that catalyses the rate-limiting step of sLe(x) synthesis. The aim here was to identify the identity of the glycoconjugate associated with sLe(x) glycoepitope in herpes simplex virus type 1 (HSV-1) infected human diploid fibroblasts, using immunofluorescence confocal microscopy. Cells infected with all tested HSV-1 strains analysed demonstrated bright sLe(x) fluorescence, except for two mutant viruses that were unable to induce proper expression of viral glycoprotein gC-1: One gC-1 null mutant and another mutant expressing gC-1 devoid of its major O-glycan-containing region (aa 33-116). The sLe(x) reactivity of HSV-1 infected cells was abolished by mild alkali treatment. Altogether the results indicated that the detectable sLe(x) was associated with O-linked glycans, situated in the mucin region of gC-1. No evidence for sLe(x) (i) in other HSV-1 glycoproteins with mucin domains such as gI-1 or (ii) in host cell glycoproteins/glycolipids was found. Thus, the mucin domain of HSV-1 gC-1 may support expression of selectin ligands such as sLe(x) and other larger O-linked glycans in cell types lacking endogenous mucin domain-containing glycoproteins, optimized for O-glycan expression, provided that the adequate host glycosyltransferase genes are activated.
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5.
  • Nordén, Rickard, 1977, et al. (author)
  • NF kappa B-mediated activation of the cellular FUT3, 5 and 6 gene cluster by herpes simplex virus type 1
  • 2017
  • In: Glycobiology. - : Oxford University Press (OUP). - 0959-6658 .- 1460-2423. ; 27:11, s. 999-1005
  • Journal article (peer-reviewed)abstract
    • Herpes simplex virus type 1 has the ability to induce expression of a human gene cluster located on chromosome 19 upon infection. This gene cluster contains three fucosyltransferases (encoded by FUT3, FUT5 and FUT6) with the ability to add a fucose to an N-acetylglucosamine residue. Little is known regarding the transcriptional activation of these three genes in human cells. Intriguingly, herpes simplex virus type 1 activates all three genes simultaneously during infection, a situation not observed in uninfected tissue, pointing towards a virus specific mechanism for transcriptional activation. The aim of this study was to define the underlying mechanism for the herpes simplex virus type 1 activation of FUT3, FUT5 and FUT6 transcription. The transcriptional activation of the FUT-gene cluster on chromosome 19 in fibroblasts was specific, not involving adjacent genes. Moreover, inhibition of NF kappa B signaling through panepoxydone treatment significantly decreased the induction of FUT3, FUT5 and FUT6 transcriptional activation, as did siRNA targeting of p65, in herpes simplex virus type 1 infected fibroblasts. NF kappa B and p65 signaling appears to play an important role in the regulation of FUT3, FUT5 and FUT6 transcriptional activation by herpes simplex virus type 1 although additional, unidentified, viral factors might account for part of the mechanism as direct interferon mediated stimulation of NF kappa B was not sufficient to induce the fucosyltransferase encoding gene cluster in uninfected cells.
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6.
  • Nordén, Rickard, 1977, et al. (author)
  • O-linked glycosylation of the mucin domain of the herpes simplex virus type 1 specific glycoprotein gC-1 is temporally regulated in a seed-and-spread manner.
  • 2015
  • In: The Journal of biological chemistry. - 1083-351X. ; 290:8, s. 5078-5091
  • Journal article (peer-reviewed)abstract
    • The herpes simplex virus type 1 (HSV-1) glycoprotein gC-1, participating in viral receptor interactions and immunity interference, harbors a mucin-like domain with multiple clustered O-linked glycans. Using HSV-1 infected diploid human fibroblasts, an authentic target for HSV-1 infection, and a protein immunoaffinity procedure, we enriched fully glycosylated gC-1 and a series of its biosynthetic intermediates. This fraction was subjected to trypsin digestion and a LC-MS/MS glycoproteomics approach. In parallel, we characterized the expression patterns of the 20 isoforms of human GalNAc transferases responsible for initiation of O-linked glycosylation. The gC-1 O-glycosylation was regulated in an orderly manner initiated by synchronous addition of one GalNAc unit each to T87 and T91, and one GalNAc unit to either T99 or T101, forming a core glycopeptide for subsequent additions of in all 11 GalNAc residues to selected Ser and Thr residues of the T76-L107 stretch of the mucin domain. The expression patterns of GalNAc transferases in the infected cells suggested that initial additions of GalNAc were carried out by initiating GalNAc transferases, in particular GalNAc-T2, whereas subsequent GalNAc additions were carried out by follow up transferases, in particular GalNAc-T10. Essentially all of the susceptible Ser or Thr residues had to acquire their GalNAc units before any elongation to longer O-linked glycans of the gC-1-associated GalNAc units was permitted. Since the GalNAc occupancy pattern is of relevance for receptor binding of gC-1, the data provides a model to delineate biosynthetic steps of O-linked glycosylation of the gC-1 mucin domain in HSV-1 infected target cells.
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7.
  • Nordén, Rickard, 1977, et al. (author)
  • Virus-induced appearance of the selectin ligand sLeX in herpes simplex virus type 1-infected T cells: Involvement of host and viral factors.
  • 2013
  • In: Glycobiology. - : Oxford University Press (OUP). - 1460-2423 .- 0959-6658. ; 23:3, s. 310-321
  • Journal article (peer-reviewed)abstract
    • Circulating leukocytes that express selectin ligands such as the carbohydrate epitope sialyl Lewis X (sLeX) may interact with endothelial selectins, resulting in transmigration of the leukocyte across the endothelial wall to adjacent tissue. Due to the potential of selectin-ligand interactions as targets in viral pathogenesis, we aimed at determining whether herpes simplex virus type 1 (HSV1) is able to induce appearance of sLeX at the surface of infected leukocytes. We found that HSV1 infection of a T cell line resulted in transcriptional activation of human fucosyltransferase genes FUT3, FUT6 and FUT7, the two latter genes encoding fucosyltransferases rate limiting for sLeX synthesis. Flow cytometry and confocal microscopy demonstrated that HSV1 infection resulted in a two-fold rise in the proportion of sLeX-positive cells. Increased levels of FUT3, FUT6 and FUT7 RNA were detected already at 3 h post infection, and treatment with cycloheximide, a translation inhibitor, blocked HSV1-induced increase in expression of FUT3, FUT6 and FUT7 RNA, suggesting involvement of viral or cellular proteins. Studies with infectious viral mutants indicated that the viral immediate early (α) protein ICP0 is essential for initiation of FUT7 though not for FUT3 or FUT6 transcription. In CD3+ cells, derived from peripheral blood mononuclear cells, HSV1 infection induced expression of FUT3, FUT5 and FUT6, whereas FUT7 was not altered. The mean sLeX fluorescence intensity of CD3+ cells was significantly higher in HSV1-infected CD3+ cells. This suggests that infected leukocytes during HSV1 viremia may express selectin ligands with possible but as yet unproven roles in viral pathogenesis.
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8.
  • Nyström, Kristina, 1977, et al. (author)
  • Induction of sialyl-Lex expression by herpes simplex virus type 1 is dependent on viral immediate early RNA-activated transcription of host fucosyltransferase genes. : Induction of sialyl-Lewis x expression by HSV-1
  • 2009
  • In: Glycobiology. - : Oxford University Press (OUP). - 1460-2423 .- 0959-6658. ; 19:8, s. 847-59
  • Journal article (peer-reviewed)abstract
    • We have previously shown that varicella-zoster virus (VZV) and cytomegalovirus (CMV) infection of diploid human fibroblasts (HEL) results in neo-expression of Lewis antigens sialyl Lewis x (sLe(x)) and Lewis y (Le(y)), respectively, after transcriptional activation of different combinations of dormant human fucosyltransferase genes (FUT1, FUT3, FUT5, and FUT6), whose gene products are responsible for the synthesis of Le antigens. Here, we show that herpes simplex virus type 1 (HSV-1) also induces sLe(x) expression dependent on induction of FUT3, FUT5, and FUT6 transcription in infected cells. HSV-1 induction of FUT5 was subsequently used as a model system for analyzing the mechanism of viral activation of dormant fucosyltransferase genes. We show that this is a rapid process, which gives rise to elevated FUT5 RNA levels already at 90 min postinfection. Augmented FUT5 transcription was found to be dependent on transcription of viral genes, but not dependent on the immediate early proteins ICP0 and ICP4, as demonstrated by experiments with HSV-1 mutants defective in expression of these genes. Augmented FUT5 transcription takes place in cycloheximide-treated HSV-1-infected cells, suggesting a more direct role for IE viral RNA during activation of cellular FUT5.
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9.
  • Samuelsson, Ebba, 1991, et al. (author)
  • Sialic Acid and Fucose Residues on the SARS-CoV-2 Receptor-Binding Domain Modulate IgG Antibody Reactivity
  • 2022
  • In: Acs Infectious Diseases. - : American Chemical Society (ACS). - 2373-8227. ; 8:9, s. 1883-1893
  • Journal article (peer-reviewed)abstract
    • The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein is a conserved domain and a target for neutralizing antibodies. We defined the carbohydrate content of the recombinant RBD produced in different mammalian cells. We found a higher degree of complex-type N-linked glycans, with less sialylation and more fucosylation, when the RBD was produced in human embryonic kidney cells compared to the same protein produced in Chinese hamster ovary cells. The carbohydrates on the RBD proteins were enzymatically modulated, and the effect on antibody reactivity was evaluated with serum samples from SARS-CoV-2 positive patients. Removal of all carbohydrates diminished antibody reactivity, while removal of only sialic acids or terminal fucoses improved the reactivity. The RBD produced in Lec3.2.8.1-cells, which generate carbohydrate structures devoid of sialic acids and with reduced fucose content, exhibited enhanced antibody reactivity, verifying the importance of these specific monosaccharides. The results can be of importance for the design of future vaccine candidates, indicating that it is possible to enhance the immunogenicity of recombinant viral proteins.
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10.
  • Sengpiel, Verena, 1977, et al. (author)
  • Confirmed reinfection with SARS-CoV-2 during a pregnancy: A case report.
  • 2022
  • In: Clinical case reports. - : Wiley. - 2050-0904. ; 10:2
  • Journal article (peer-reviewed)abstract
    • Pregnancy might impact immunity after SARS-CoV-2 infection and/or vaccination. We describe the first case of reinfection with SARS-CoV-2 during a pregnancy. While the mother lacked detectable antibodies 2months after the first infection, both mother and baby had IgG antibodies at delivery. Infection did not cause any adverse pregnancy outcome.
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11.
  • Adelöf, Anna, et al. (author)
  • Förvaltning av SNOMED CT som en del i det nationella fackspråket för vård och omsorg
  • 2011
  • Reports (pop. science, debate, etc.)abstract
    • Förvaltningsrapporten fokuserar på Snomed CT, eftersom det redan i dag finns rutiner för förvaltningar av termbanken och nationella hälsorelaterade klassifikationer. Ett särskilt utvecklingsarbete kommer att krävas för dessa delar.Rapporten tar upp syfte och mål med förvaltningen. Utöver det redogör rapporten för vilka konkreta ansvarsområden som ingår i förvaltningen av Snomed CT. Målet för förvaltningen är att Socialstyrelsen regelbundet ska kunna tillhandahålla en kontrollerad och uppdaterad release av Snomed CT. Det skulle möjliggöra användning inom vård och omsorg. Rapporten tar även upp behovet av kompetens, utbildning och finansiella resurser.
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12.
  • Alsved, Malin, et al. (author)
  • Infectivity of exhaled SARS-CoV-2 aerosols is sufficient to transmit covid-19 within minutes
  • 2023
  • In: Scientific Reports. - 2045-2322. ; 13
  • Journal article (peer-reviewed)abstract
    • Exhaled SARS-CoV-2-containing aerosols contributed significantly to the rapid and vast spread of covid-19. However, quantitative experimental data on the infectivity of such aerosols is missing. Here, we quantified emission rates of infectious viruses in exhaled aerosol from individuals within their first days after symptom onset from covid-19. Six aerosol samples from three individuals were culturable, of which five were successfully quantified using TCID50. The source strength of the three individuals was highest during singing, when they exhaled 4, 36, or 127 TCID50/s, respectively. Calculations with an indoor air transmission model showed that if an infected individual with this emission rate entered a room, a susceptible person would inhale an infectious dose within 6 to 37 min in a room with normal ventilation. Thus, our data show that exhaled aerosols from a single person can transmit covid-19 to others within minutes at normal indoor conditions.
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13.
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14.
  • Barlow, Lotti, et al. (author)
  • Nationellt fackspråk för vård och omsorg : Slutrapport
  • 2011
  • Reports (pop. science, debate, etc.)abstract
    • SammanfattningEtt tillgängligt och använt nationellt fackspråk ska bidra till en god och säker vård och omsorg. Det ska även medverka till att kvaliteten och resultaten på området ska kunna följas upp och jämföras på ett mer effektivt sätt. Slutrapporten presenterar resultatet av projektet Nationellt fackspråk för vård och omsorg samt förslag till förvaltning och utveckling.ResultatetResultatet innefattar bland annat att det internationella begreppssystemet Snomed CT är översatt till svenska och att det är förberett för förvaltning och distribution. Socialstyrelsen har även tagit fram och testat metoder för förvaltning och utveckling av det nationella fackspråket i sin helhet. Därtill har representanter för målgrupperna informerats och fått kunskap.Rapporten innehåller en utförlig beskrivning av det nationella fackspråkets sammantagna innehåll: Socialstyrelsens termbank, klassifikationer och kodverk, den svenska versionen av Snomed CT, metoder för utveckling och förvaltning samt regler för användning.Förvaltning, införande och resursbehovI rapporten finns förslag till hur hela det nationella fackspråket kan tas omhand av Socialstyrelsen och hur det kan införas i vården och omsorgen. Projektets övergång till en långsiktigt hållbar organisation kräver resurser. Därför redogör rapporten för det förväntade resursbehovet för förvaltning och utveckling. Bland annat föreslås en treårig utbildningsinsats samt stimulansbidrag för införande.Krav på styrning, samordning och förtydligat ansvarRapporten betonar behovet av en samlad och medveten styrning av utvecklingen inom området. Socialstyrelsen vill ha en samordnande roll i utvecklingen och förvaltningen av det nationella fackspråket. Myndigheten föreslås få det initiala ansvaret för att utbilda användare och att driva frågor om det nationella fackspråket.Vidare vill Socialstyrelsen få ett uttalat mandat att samordna de nationella aktiviteter som drivs med koppling till Snomed CT. Rapporten pekar ut några särskilt prioriterade områden som myndigheten borde få i uppdrag att arbeta vidare inom.Kunskapsstyrning och normgivningEn viktig slutsats i rapporten är att användningen av det nationella fackspråket behöver regleras för att målet om ökad säkerhet för klienter och patienter ska kunna uppnås. I dagsläget bedöms föreskrifter vara den metod som bäst kan garantera ett brett genomförande.Målgrupper för slutrapportenSlutrapporten riktar sig till beslutsfattare i kommuner och landsting, vård- och omsorgspersonal med särskilt intresse eller ansvar för dokumentationsfrågor och professionella organisationer. Den riktar sig också till terminologiansvariga i kommuner och landsting, IT-direktörer, IT-leverantörer samt aktörer inom den nationella strategin för eHälsa.
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15.
  • Beck-Friis, Thomas, et al. (author)
  • Comparison of SARS-CoV-2 spike RNA sequences in feces and nasopharynx indicates intestinal replication
  • 2022
  • In: Gut Pathogens. - : Springer Science and Business Media LLC. - 1757-4749. ; 14:1
  • Journal article (peer-reviewed)abstract
    • Background Little is known of possible selection and replication of SARS-CoV-2 in the intestines and if viral load in feces is associated with severity of disease. Therefore, sequence variations of the spike region in strains collected from feces and nasopharynx (NPH) from the same patients were compared. It was also investigated whether viral load in feces related to severity of COVID-19 in hospitalized patients. Results SARS-CoV-2 RNA was found in 88 (79%) fecal samples from 112 patients. The complete spike region could be sequenced in 15 fecal and 14 NPH samples. Fourteen Alpha-variants and one Beta-variant of SARS-CoV-2 were identified. The majority of the viral genetic variants (viral populations) in two fecal samples, but none in NPH, had a reversion of the H69/V70 amino acid deletion normally seen in the Alpha variants. Nine fecal samples contained up to nine minority variants, each which may constitute a separate viral population. Five NPH samples had one genetic variant each, and one NPH sample contained nine minority populations of SARS-CoV-2 spike genes. Conclusions The higher genomic diversity of SARS-CoV-2 in feces compared to NPH, and the reversion of the H69/V70 deletion in Alpha variants from feces indicate a selection of viral strains and replication of SARS-CoV-2 in the gastrointestinal tract.
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16.
  • Choong, Oi Kuan, 1985, et al. (author)
  • SARS-CoV-2 replicates and displays oncolytic properties in clear cell and papillary renal cell carcinoma
  • 2023
  • In: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 18:1
  • Journal article (peer-reviewed)abstract
    • The SARS-CoV-2 virus is currently causing a global pandemic. Infection may result in a systemic disease called COVID-19, affecting primarily the respiratory tract. Often the gastrointestinal tract and kidneys also become involved. Angiotensin converting enzyme 2 (ACE2) serves as the receptor for SARS-CoV-2. The membrane proteins, Transmembrane serine protease 2 (TMPRSS2) and Neuropilin 1 (NRP1) are accessory proteins facilitating the virus entry. In this study we show that the human proximal kidney tubules, express these factors. We hypothesized that cancers derived from proximal tubules as clear cell (CCRCC) and papillary renal cell carcinoma (PRCC), retain the expression of the SARS-CoV-2 entry factors making these cancers susceptible to SARS-CoV-2 infection. We used bioinformatics, western blotting, and assessment of tissue micro arrays (TMA) including 263 cases of CCRCC, 139 cases of PRCC and 18 cases of chromophobe RCC to demonstrate that the majority of CCRCC and PRCC cases retained the RNA and protein expression of the entry factors for SARS-CoV-2. We furthermore show that SARS-CoV-2 virus propagated robustly in primary cultures of CCRCC and PRCC cells with a visible virus cytopathogenic effect correlating with viral RNA expression levels. We also noted that the delta-variant of SARS-CoV-2 causes cancer cells to form syncytia in-vitro. This phenomenon was also identified histologically in CCRCC tissue from a patient that had been hospitalized for COVID-19, twelve months prior to nephrectomy. Our data provide insights into SARS-CoV-2 infectivity in renal cell carcinoma and that the virus causes a distinct cytopathogenic effect.
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17.
  • Ebefors, Kerstin, 1977, et al. (author)
  • Mesangial cells from patients with IgA nephropathy have increased susceptibility to galactose-deficient IgA1
  • 2016
  • In: Bmc Nephrology. - : Springer Science and Business Media LLC. - 1471-2369. ; 17
  • Journal article (peer-reviewed)abstract
    • Background: IgA nephropathy (IgAN) is the most common glomerulonephritis in the world, affecting close to a million people. Circulating galactose-deficient IgA (gd-IgA), present in patients with IgAN, form immune complex deposits in the glomerular mesangium causing local proliferation and matrix expansion. Intriguing though, individuals having gd-IgA deposits in the kidneys do not necessarily have signs of glomerular disease. Recurrence of IgAN only occurs in less than half of transplanted patients with IgAN, indicating that gd-IgA is not the only factor driving the disease. We hypothesize that, in addition to IgA complexes, patients with IgAN possess a subtype of mesangial cells highly susceptible to gd-IgA induced cell proliferation. Methods: To test the hypothesis, we designed a technique to culture primary mesangial cells from renal biopsies obtained from IgAN patients and controls. The cell response to gd-IgA treatment was then measured both on gene and protein level and the proliferation rate of the cells in response to PDGF was investigated. Results: When treated with gd-IgA, mesangial cells from patients with IgAN express and release more PDGF compared to controls. In addition, the mesangial cells from patients with IgAN were more responsive to treatment with PDGF resulting in an increased proliferation rate of the cells compared to control. Mesangial cells cultured from patients with IgAN expressed and released more IL-6 than controls and had a higher expression of matrix genes. Both mesangial cells derived from patients with IgAN and controls increased their expressed TGF beta 1 and CCL5 when treated with gd-IgA. Conclusion: We conclude that mesangial cells derived from IgAN patients have a mesangioproliferative phenotype with increased reactivity to IgA and that these cellular intrinsic properties may be important for the development of IgA nephropathy.
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18.
  • Guimond, S. E., et al. (author)
  • Synthetic Heparan Sulfate Mimetic Pixatimod (PG545) Potently Inhibits SARS-CoV-2 by Disrupting the Spike-ACE2 Interaction
  • 2022
  • In: ACS Central Science. - : American Chemical Society (ACS). - 2374-7943 .- 2374-7951. ; 8:5, s. 527-545
  • Journal article (peer-reviewed)abstract
    • Heparan sulfate (HS) is a cell surface polysaccharide recently identified as a coreceptor with the ACE2 protein for the S1 spike protein on SARS-CoV-2 virus, providing a tractable new therapeutic target. Clinically used heparins demonstrate an inhibitory activity but have an anticoagulant activity and are supply-limited, necessitating alternative solutions. Here, we show that synthetic HS mimetic pixatimod (PG545), a cancer drug candidate, binds and destabilizes the SARS-CoV-2 spike protein receptor binding domain and directly inhibits its binding to ACE2, consistent with molecular modeling identification of multiple molecular contacts and overlapping pixatimod and ACE2 binding sites. Assays with multiple clinical isolates of SARS-CoV-2 virus show that pixatimod potently inhibits the infection of monkey Vero E6 cells and physiologically relevant human bronchial epithelial cells at safe therapeutic concentrations. Pixatimod also retained broad potency against variants of concern (VOC) including B.1.1.7 (Alpha), B.1.351 (Beta), B.1.617.2 (Delta), and B.1.1.529 (Omicron). Furthermore, in a K18-hACE2 mouse model, pixatimod significantly reduced SARS-CoV-2 viral titers in the upper respiratory tract and virus-induced weight loss. This demonstration of potent anti-SARS-CoV-2 activity tolerant to emerging mutations establishes proof-of-concept for targeting the HS-Spike protein-ACE2 axis with synthetic HS mimetics and provides a strong rationale for clinical investigation of pixatimod as a potential multimodal therapeutic for COVID-19.
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19.
  • Hansen, J. F., et al. (author)
  • PRO-C3: a new and more precise collagen marker for liver fibrosis in patients with chronic hepatitis C
  • 2018
  • In: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 53:1, s. 83-87
  • Journal article (peer-reviewed)abstract
    • Objective: Detecting significant fibrosis and cirrhosis remains important in treatment and follow-up of patients with chronic hepatitis C Infection (CHC). The aim of this study was to assess the ability of PRO-C3 to identify significant fibrosis (Ishak score3) and cirrhosis (Ishak score5) both as a single test and as a part of algorithms.Materials and methods: PRO-C3 was assessed in baseline samples from the NORDynamIC trial. 270 patients were stratified into groups according to baseline biopsy. Baseline APRI, FIB-4 and GUCI scores were available for comparison in 232 patients.Results: PRO-C3 increased with Ishak scores (p=.001). Area under the curve (AUC) for significant fibrosis was 0.75 (95% CI 0.68-0.81) and 0.76 (95% CI 0.68-0.84) for cirrhosis. FIB-4, APRI and GUCI had similar AUCs. In a PRO-C3 algorithm including age, platelet count, body mass index (BMI) and international normalised ratio (INR), the diagnostic efficacy improved to 0.85 (CI 0.80-0.89) and 0.90 (IQR 0.84-0.96) for significant fibrosis and cirrhosis, respectively.Conclusions: In our study, PRO-C3 was an independent predictor of fibrosis stage, and may play an important role in managing CHC patients.
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20.
  • Jennische, Eva, 1949, et al. (author)
  • The peptide AF-16 abolishes sickness and death at experimental encephalitis by reducing increase of intracranial pressure.
  • 2008
  • In: Brain research. - : Elsevier BV. - 0006-8993. ; 1227, s. 189-97
  • Journal article (peer-reviewed)abstract
    • Elevated intracranial pressure (ICP) is strongly aggravating the injury at brain inflammation, resulting in persistent neurological and psychiatric malfunctions. There is no efficient pharmacological treatment to achieve beneficial ICP reduction. Here, the peptide AF-16, comprising the amino terminal part of the endogenous protein Antisecretory Factor (AF), was used to suppress the raised ICP in experimental herpes simplex encephalitis (HSE) in rats. Intranasal instillation of the peptide AF-16 counteracted the ICP elevation and the prevalence of ICP spikes, abrogated the neurological morbidity, and abolished the mortality in a dose-dependent manner. AF-16, 25 microg twice daily intranasally, rescued all animals with HSE and abrogated neurological malfunction. In contrast, only 10% of the rats survived if treated with the vehicle. A single intranasal dose of 25 microg AF-16 to a rat displaying overt HSE symptoms reduced the ICP to normal levels within an hour. No effects on viral replication or antigen distribution were demonstrable. Thus, AF-16 abolished the prevalence of sickness signs, ICP elevation, neurological malfunctions and completely prevented deaths. We advocate use of AF-16 for suppression of elevated ICP.
  •  
21.
  • Lagging, Martin, 1965, et al. (author)
  • Reply.
  • 2014
  • In: Hepatology (Baltimore, Md.). - : Ovid Technologies (Wolters Kluwer Health). - 1527-3350 .- 0270-9139. ; 60:6, s. 2130-1
  • Journal article (other academic/artistic)
  •  
22.
  • Le Pendu, Jacques, et al. (author)
  • Host-pathogen co-evolution and glycan interactions
  • 2014
  • In: Current Opinion in Virology. - : Elsevier BV. - 1879-6257 .- 1879-6265. ; 7, s. 88-94
  • Research review (peer-reviewed)abstract
    • Noroviruses and rotavirus A bind to polymorphic glycans of the histo-blood group type (HBGAs). Norovirus strains that bind to HBGAs can collectively infect all humans but each strain only infects a subgroup of the population, suggesting a past co-evolution that led to a trade-off where the human population is partly protected whilst the virus circulation is maintained. We termed 'Herd Innate Protection' the host species partial protection provided by the HBGAs polymorphism. Given its recent emergence, high virulence and HBGAs attachment, RHDV provides a model for studying calicivirus-host co-evolution. Field observations documented evolution of the virus ability to recognize the host HBGAs diversity and reciprocal strain-dependent selection of HBGA phenotypes following outbreaks, indicating host-pathogen co-evolution involving glycan polymorphisms.
  •  
23.
  • Lopes, A. M., et al. (author)
  • Host-Specific Glycans Are Correlated with Susceptibility to Infection by Lagoviruses, but Not with Their Virulence
  • 2018
  • In: Journal of Virology. - : American Society for Microbiology. - 0022-538X .- 1098-5514. ; 92:4
  • Journal article (peer-reviewed)abstract
    • Rabbit hemorrhagic disease virus (RHDV) and European brown hare syndrome virus (EBHSV) are two lagoviruses from the family Caliciviridae that cause fatal diseases in two leporid genera, Oryctolagus and Lepus, respectively. In the last few years, several examples of host jumps of lagoviruses among leporids were recorded. In addition, a new pathogenic genotype of RHDV emerged, and many nonpathogenic strains of lagoviruses have been described. The molecular mechanisms behind host shifts and the emergence of virulence are unknown. Since RHDV uses glycans of the histo-blood group antigen type as attachment factors to initiate infection, we studied if glycan specificities of the new pathogenic RHDV genotype, nonpathogenic lagoviruses, and EBHSV potentially play a role in determining the host range and virulence of lagoviruses. We observed binding to A, B, or H antigens of the histo-blood group family for all strains known to primarily infect European rabbits (Oryctolagus cuniculus), which have recently been classified as GI strains. However, we could not explain the emergence of virulence, since similar glycan specificities were found in several pathogenic and nonpathogenic strains. In contrast, EBHSV, recently classified as GII. 1, bound to terminal beta -linked N-acetylglucosamine residues of O-glycans. Expression of these attachment factors in the upper respiratory and digestive tracts in three lagomorph species (Oryctolagus cuniculus, Lepus europaeus, and Sylvilagus floridanus) showed species-specific patterns regarding susceptibility to infection by these viruses, indicating that species-specific glycan expression is likely a major contributor to lagovirus host specificity and range. IMPORTANCE Lagoviruses constitute a genus of the family Caliciviridae comprising highly pathogenic viruses, RHDV and EBHSV, that infect rabbits and hares, respectively. Recently, nonpathogenic strains were discovered and new pathogenic strains have emerged. In addition, host jumps between lagomorphs have been observed. The mechanisms responsible for the emergence of pathogenicity and host species range are unknown. Previous studies showed that RHDV strains attach to glycans expressed in the upper respiratory and digestive tracts of rabbits, the likely portals of virus entry. Here, we studied the glycan-binding properties of novel pathogenic and nonpathogenic strains looking for a link between glycan binding and virulence or between glycan specificity and host range. We found that glycan binding did not correlate with virulence. However, expression of glycan motifs in the upper respiratory and digestive tracts of lagomorphs revealed species-specific patterns associated with the host ranges of the virus strains, suggesting that glycan diversity contributes to lagovirus host ranges.
  •  
24.
  • Lundgren, Anna, 1974, et al. (author)
  • Plasmablasts in previously immunologically naive COVID-19 patients express markers indicating mucosal homing and secrete antibodies cross-reacting with SARS-CoV-2 variants and other beta-coronaviruses
  • 2023
  • In: Clinical and Experimental Immunology. - 0009-9104 .- 1365-2249. ; 213:2, s. 173-89
  • Journal article (peer-reviewed)abstract
    • Antigen-specific class-switched antibodies are detected at the same time or even before IgM in serum of non-vaccinated individuals infected with SARS-CoV-2. These derive from the first wave of plasmablasts formed. Hence, the phenotype and specificity of plasmablasts can reveal information about early B-cell activation. Here we have analyzed B cells and plasmablasts circulating in blood of COVID-19 patients not previously exposed to SARS-CoV-2 during and after disease. We find that during infection with the original Wuhan strain, plasmablasts in blood produce IgA1, IgG1, and IgM, and that most express CCR10 and integrin beta 1, only some integrin beta 7, while the majority lack CCR9. Plasmablast-secreted antibodies are reactive to the spike (S) and nucleocapsid (N) proteins of the Wuhan strain as well as later variants of concern, but also bind S proteins from endemic and non-circulating betacoronaviruses. In contrast, after recovery, antibodies produced from memory B cells target variants of SARS-CoV-2 and SARS-CoV-1 but compared to previously non-infected individuals do not show increased binding to endemic coronaviruses. This suggests that the early antibody response to a large extent stems from pre-existing cross-reactive class-switched memory B cells, and that although newly formed memory cells target the novel SARS-CoV-2 virus the numbers of broadly cross-reactive memory B cells do not increase extensively. The observations give insight into the role of pre-existing memory B cells in early antibody responses to novel pathogens and may explain why class-switched antibodies are detected early in the serum of COVID-19 patients. During an infection, plasmablasts circulating in blood represent ongoing formation of antibody-producing cells from activated B cells. Here we study the early plasmablasts in previously naive COVID-19 patients arriving at hospital. We find extensive cross-reactivity to circulating and non-circulating beta-coronaviruses, that IgA1 responses dominate, and that the cells express markers suggesting mucosal homing.
  •  
25.
  • Marklund, Emelie, et al. (author)
  • Longitudinal Follow Up of Immune Responses to SARS-CoV-2 in Health Care Workers in Sweden With Several Different Commercial IgG-Assays, Measurement of Neutralizing Antibodies and CD4+ T-Cell Responses.
  • 2021
  • In: Frontiers in immunology. - : Frontiers Media SA. - 1664-3224. ; 12
  • Journal article (peer-reviewed)abstract
    • The risk of SARS-CoV-2 infection among health care workers (HCWs) is a concern, but studies that conclusively determine whether HCWs are over-represented remain limited. Furthermore, methods used to confirm past infection vary and the immunological response after mild COVID-19 is still not well defined.314 HCWs were recruited from a Swedish Infectious Diseases clinic caring for COVID-19 patients. IgG antibodies were measured using two commercial assays (Abbot Architect nucleocapsid (N)-assay and YHLO iFlash-1800 N and spike (S)-assays) at five time-points, from March 2020 to January 2021, covering two pandemic waves. Seroprevalence was assessed in matched blood donors at three time-points. More extensive analyses were performed in 190 HCWs in September/October 2020, including two additional IgG-assays (DiaSorin LiaisonXL S1/S2 and Abbot Architect receptor-binding domain (RBD)-assays), neutralizing antibodies (NAbs), and CD4+ T-cell reactivity using an in-house developed in vitro whole-blood assay based on flow cytometric detection of activated cells after stimulation with Spike S1-subunit or Spike, Membrane and Nucleocapsid (SMN) overlapping peptide pools.Seroprevalence was higher among HCWs compared to sex and age-matched blood donors at all time-points. Seropositivity increased from 6.4% to 16.3% among HCWs between May 2020 and January 2021, compared to 3.6% to 11.9% among blood donors. We found significant correlations and high levels of agreement between NAbs and all four commercial IgG-assays. At 200-300 days post PCR-verified infection, there was a wide variation in sensitivity between the commercial IgG-assays, ranging from <30% in the N-assay to >90% in the RBD-assay. There was only moderate agreement between NAbs and CD4+ T-cell reactivity to S1 or SMN. Pre-existing CD4+ T-cell reactivity was present in similar proportions among HCW who subsequently became infected and those that did not.HCWs in COVID-19 patient care in Sweden have been infected with SARS-CoV-2 at a higher rate compared to blood donors. We demonstrate substantial variation between different IgG-assays and propose that multiple serological targets should be used to verify past infection. Our data suggest that CD4+ T-cell reactivity is not a suitable measure of past infection and does not reliably indicate protection from infection in naive individuals.
  •  
26.
  • Marklund, Emelie, et al. (author)
  • Serum-IgG responses to SARS-CoV-2 after mild and severe COVID-19 infection and analysis of IgG non-responders.
  • 2020
  • In: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 15:10
  • Journal article (peer-reviewed)abstract
    • To accurately interpret COVID-19 seroprevalence surveys, knowledge of serum-IgG responses to SARS-CoV-2 with a better understanding of patients who do not seroconvert, is imperative. This study aimed to describe serum-IgG responses to SARS-CoV-2 in a cohort of patients with both severe and mild COVID-19, including extended studies of patients who remained seronegative more than 90 days post symptom onset.SARS-CoV-2-specific IgG antibody levels were quantified using two clinically validated and widely used commercial serological assays (Architect, Abbott Laboratories and iFlash 1800, YHLO), detecting antibodies against the spike and nucleocapsid proteins.Forty-seven patients (mean age 49 years, 38% female) were included. All (15/15) patients with severe symptoms and 29/32 (90.6%) patients with mild symptoms of COVID-19 developed SARS-CoV-2-specific IgG antibodies in serum. Time to seroconversion was significantly shorter (median 11 vs. 22 days, P = 0.04) in patients with severe compared to mild symptoms. Of the three patients without detectable IgG-responses after >90 days, all had detectable virus-neutralizing antibodies and in two, spike-protein receptor binding domain-specific IgG was detected with an in-house assay. Antibody titers were preserved during follow-up and all patients who seroconverted, irrespective of the severity of symptoms, still had detectable IgG levels >75 days post symptom onset.Patients with severe COVID-19 both seroconvert earlier and develop higher concentrations of SARS-CoV-2-specific IgG than patients with mild symptoms. Of those patients who not develop detectable IgG antibodies, all have detectable virus-neutralizing antibodies, suggesting immunity. Our results showing that not all COVID-19 patients develop detectable IgG using two validated commercial clinical methods, even over time, are vital for the interpretation of COVID-19 seroprevalence surveys.
  •  
27.
  • Nordén, Rickard, 1977, et al. (author)
  • Inhibition of protein deacetylation augments herpes simplex virus type 1-activated transcription of host fucosyltransferase genes associated with virus-induced sLex expression.
  • 2010
  • In: Archives of virology. - : Springer Science and Business Media LLC. - 1432-8798 .- 0304-8608. ; 155:3, s. 305-13
  • Journal article (peer-reviewed)abstract
    • Herpes simplex virus type 1 induces expression of the selectin ligand sialyl Lewis X in infected cells by activating transcription of three normally silent host glycosyltransferase genes, FUT3, FUT5, and FUT6, a process that is initiated by binding of viral RNA to cellular protein kinase R. We investigated the involvement of protein deacetylation and promoter methylation in viral activation of host FUT genes by analysing the effects of appropriate inhibitors on the transcription rates of the FUT genes in virus-infected cells. The histone deacetylase inhibitor trichostatin A augmented the viral activation of FUT transcription, whereas inhibition of DNA methylation did not affect transcription of these genes. The trichostatin A enhancement did not involve interference with expression of viral late genes or viral DNA replication. Thus, the virus-activated FUT genes are at least partially suppressed by deacetylation of histones or other regulatory proteins in uninfected HEL cells, whereas promoter methylation is a less important factor.
  •  
28.
  • Norder, Helene, et al. (author)
  • Hepatitis E Virus Genotype 3 Genomes from RNA-Positive but Serologically Negative Plasma Donors Have CUG as the Start Codon for ORF3
  • 2018
  • In: Intervirology. - : S. Karger AG. - 0300-5526 .- 1423-0100. ; 61:2, s. 96-103
  • Journal article (peer-reviewed)abstract
    • Hepatitis E virus (HEV) is a pathogen that causes hepatitis worldwide. Molecular studies have identified HEV RNA in blood products although its significance is not understood. This study was undertaken to characterize HEV genomes in asymptomatic plasma donors from Sweden and Germany lacking anti-HEV. Complete open reading frames (ORFs) were obtained from HEV strains in 5 out of 18 plasma donors who tested positive for HEV RNA. All strains had CUG as the start codon of ORF3, while 147 GenBank strains all had AUG as the start codon (p < 0.0001). This substitution was found in both interrelated and unrelated strains belonging to different phylogenetic clades. The HEV strains from the seronegative plasma donors had no other substitution in common, which may be why the CUG substitution seems to ex- plain the seronegativity. (C) 2018 The Author(s) Published by S. Karger AG, Basel
  •  
29.
  • Nyström, Kristina, 1977 (author)
  • Herpesvirus-induced expression of sLe(x) and related O-linked glycans in the infected cell
  • 2007
  • Doctoral thesis (other academic/artistic)abstract
    • Lewis antigens constitute a family of fucosylated carbohydrate antigens (glycotopes), involved in leukocyte homing and related immunological phenomena. These glycotopes are only expressed restrictedly in normal cells, but are induced at appropriate occasions. It is well established that many tumors ?hijack? Lewis glycotopes for e.g. extravasation and metastasis, and recent data indicate that also human retroviruses may use a similar strategy for colonization of distal tissues. The overall goal of the present thesis was to explore the prerequisite for this phenomenon to occur in cells infected with herpesviruses, a virus family where persistent infections and immune evasion are important hallmarks. Using confocal immunofluorescence, neo-expression of Lewis antigens was found on cells infected with herpes simplex virus type-1 (HSV-1), varicella-zoster virus (VZV), and cytomegalovirus (CMV). However, whereas the neurotropic viruses VZV and HSV-1 induced sialyl Lewis x (sLex), CMV induced Lewis y (Ley) at the surface of the infected cells. Real time RT-PCR methods for transcriptional analysis of all known human fucosyltransferase genes (FUT) were developed to determine the mechanism behind virus-specific induction of different glycotopes. The herpesviruses investigated were all able to induce transcription of FUT3, FUT5 and FUT6 relevant for sLex and Ley synthesis whereas only CMV induced FUT1, necessary for Ley expression. In most cases the transcriptional activity of these genes was several orders of magnitude larger in virus-infected cells compared to uninfected cells. The viral factors causing neo-expression of glycotopes were explored using FUT5 and the HSV-1 infected cell as a model system. It was found that the transcripts of the immediate early viral gene, designated ICP0, was able to induce FUT5 transcription without assistance of the translated gene product. This finding explained the extremely early occurrence of host FUT5 RNA, detectable as early as one hour post infection. However, several other viral factors were engaged in regulation of the FUT5 transcription downstream the ICP0 induction. The viral glycoprotein gC-1 was identified as a probable candidate as a carrier of O-linked glycans and important regulatory elements of the O-glycosylation sequon of gC-1 were characterized. These regulatory elements were decisive for the social behavior of virus-infected cells in culture. The conclusion of the present work is that herpesviruses possess powerful mechanisms for viral control of the expression of selectin ligands and similar glycotopes, of relevance for tumor metastasizing and tissue invasion of human transforming retroviruses. sLex and Ley constitute targets for development of cancer chemotherapy, but further investigation is necessary to determine whether this approach is applicable also for treatment of herpesvirus-infections.
  •  
30.
  • Nyström, Kristina, 1977, et al. (author)
  • Inosine Triphosphate Pyrophosphatase Dephosphorylates Ribavirin Triphosphate and Reduced Enzymatic Activity Potentiates Mutagenesis in Hepatitis C Virus
  • 2018
  • In: Journal of Virology. - : American Society for Microbiology. - 0022-538X .- 1098-5514. ; 92:19
  • Journal article (peer-reviewed)abstract
    • A third of humans carry genetic variants of the ITP pyrophosphatase (ITPase) gene (ITPA) that lead to reduced enzyme activity. Reduced ITPase activity was earlier reported to protect against ribavirin-induced hemolytic anemia and to diminish relapse following ribavirin and interferon therapy for hepatitis C virus (HCV) genotype 2 or 3 infections. While several hypotheses have been put forward to explain the antiviral actions of ribavirin, details regarding the mechanisms of interaction between reduced ITPase activity and ribavirin remain unclear. The in vitro effect of reduced ITPase activity was assessed by means of transfection of hepatocytes (Huh7.5 cells) with a small interfering RNA (siRNA) directed against ITPA or a negative-control siRNA in the presence or absence of ribavirin in an HCV culture system. Low ribavirin concentrations strikingly depleted intracellular GTP levels in HCV-infected hepatocytes whereas higher ribavirin concentrations induced G-to-A and C-to-U single nucleotide substitutions in the HCV genome, with an ensuing reduction of HCV RNA expression and HCV core antigen production. Ribavirin triphosphate (RTP) was dephosphorylated in vitro by recombinant ITPase to a similar extent as ITP, a naturally occurring substrate of ITPase, and reducing ITPA expression in Huh 7.5 cells by siRNA increased intracellular levels of RTP in addition to increasing HCV mutagenesis and reducing progeny virus production. Our results extend the understanding of the biological impact of reduced ITPase activity, demonstrate that RTP is a substrate of ITPase, and may point to personalized ribavirin dosage according to ITPA genotype in addition to novel antiviral strategies. IMPORTANCE This study highlights the multiple modes of action of ribavirin, including depletion of intracellular GTP and increased hepatitis C virus mutagenesis. In cell culture, reduced ITP pyrophosphatase (ITPase) enzyme activity affected the intracellular concentrations of ribavirin triphosphate (RTP) and augmented the impact of ribavirin on the mutation rate and virus production. Additionally, our results imply that RTP, similar to ITP, a naturally occurring substrate of ITPase, is dephosphorylated in vitro by ITPase.
  •  
31.
  • Nyström, Kristina, 1977, et al. (author)
  • Neofunctionalization of the Sec1 alpha 1,2fucosyltransferase Paralogue in Leporids Contributes to Glycan Polymorphism and Resistance to Rabbit Hemorrhagic Disease Virus
  • 2015
  • In: Plos Pathogens. - : Public Library of Science (PLoS). - 1553-7366 .- 1553-7374. ; 11:4
  • Journal article (peer-reviewed)abstract
    • RHDV (rabbit hemorrhagic disease virus), a virulent calicivirus, causes high mortalities in European rabbit populations (Oryctolagus cuniculus). It uses alpha 1,2fucosylated glycans, histo-blood group antigens (HBGAs), as attachment factors, with their absence or low expression generating resistance to the disease. Synthesis of these glycans requires an alpha 1,2fucosyltransferase. In mammals, there are three closely located alpha 1,2fucosyltransferase genes rSec1, rFut2 and rFut1 that arose through two rounds of duplications. In most mammalian species, Sec1 has clearly become a pseudogene. Yet, in leporids, it does not suffer gross alterations, although we previously observed that rabbit Sec1 variants present either low or no activity. Still, a low activity rSec1 allele correlated with survival to an RHDV outbreak. We now confirm the association between the alpha 1,2fucosyltransferase loci and survival. In addition, we show that rabbits express homogenous rFut1 and rFut2 levels in the small intestine. Comparison of rFut1 and rFut2 activity showed that type 2 A, B and H antigens recognized by RHDV strains were mainly synthesized by rFut1, and all rFut1 variants detected in wild animals were equally active. Interestingly, rSec1 RNA levels were highly variable between individuals and high expression was associated with low binding of RHDV strains to the mucosa. Co-transfection of rFut1 and rSec1 caused a decrease in rFut1-generated RHDV binding sites, indicating that in rabbits, the catalytically inactive rSec1 protein acts as a dominant-negative of rFut1. Consistent with neofunctionalization of Sec1 in leporids, gene conversion analysis showed extensive homogenization between Sec1 and Fut2 in leporids, at variance with its limited degree in other mammals. Gene conversion additionally involving Fut1 was also observed at the C-terminus. Thus, in leporids, unlike in most other mammals where it became extinct, Sec1 evolved a new function with a dominant-negative effect on rFut1, contributing to fucosylated glycan diversity, and allowing herd protection from pathogens such as RHDV.
  •  
32.
  • Nyström, Kristina, 1977, et al. (author)
  • Real time PCR for monitoring regulation of host gene expression in herpes simplex virus type 1-infected human diploid cells
  • 2004
  • In: J Virol Methods. ; 118:2, s. 83-94
  • Journal article (peer-reviewed)abstract
    • Herpes simplex virus type 1 (HSV-1) induces prominent shifts in the rates of transcription of host cellular genes of relevance for the outcome of the viral infection. The quantitative analysis of transcription may be obscured by virus-induced alterations in the levels of RNA encoded by cellular housekeeping genes that are used commonly for normalisation of real time reverse transcription PCR (RT-qPCR). In the present study, we analysed beta-actin, GAPDH and 18S rRNA for their usefulness in normalisation of RT-qPCR analysis of the transcription of the HSV-1 gamma gB-1 gene and FUT5, a cellular gene induced by viral infection. The transcription of these genes was monitored in a TaqMan-based real time RT-PCR system over a 24h interval of virus infection of human embryonic lung fibroblasts. The levels of gB-1 and FUT5 RNA were normalised via difference in the threshold cycle (deltaC(t)) values relative to each and one of the housekeeping genes or calculated in relation to the number of infected cells without any further normalisation. The levels of RNA encoded by beta-actin or GAPDH were found to vary by several orders of magnitude during HSV-1 infection, introducing large errors in the estimation of the gB-1 and FUT5 RNA levels. In contrast, the variation of C(t) values for 18S rRNA was less than one cycle during 24h period of HSV-1 infection. The FUT5 and gB-1 RNA figures obtained by DeltaC(t) normalisation relative 18S rRNA were identical to those calculated in relation to the number of infected cells. These data recommend 18S rRNA for normalisation in HSV-1-infected human cells but discourage the use of beta-actin and GAPDH RNA for this purpose. By applying these procedures, it was shown that the transcription of FUT5 was increased by 50-fold 5-24h after HSV-1 infection and 200-fold by the inhibition of viral DNA replication in HSV-infected cells.
  •  
33.
  • Nyström, Kristina, 1977, et al. (author)
  • Ribavirin: Pharmacology, multiple modes of action and possible future perspectives
  • 2019
  • In: Future Virology. - : Future Medicine Ltd. - 1746-0794 .- 1746-0808. ; 14, s. 153-160
  • Research review (peer-reviewed)abstract
    • © 2019 2019 Martin Lagging. Ribavirin is a unique guanosine analog with broad-spectrum activity against many RNA and DNA viruses. In addition to its mutational properties, ribavirin exerts extensive perturbation of cellular and viral gene expression. Furthermore, recent advances indicate that the impact of ribavirin on divergent cellular and viral pathways may be concentration dependent. This review aims at providing an overview of the pharmacology and multiple modes of action of ribavirin as well as pointing to possible novel future uses.
  •  
34.
  • Nyström, Kristina, 1977, et al. (author)
  • Virus-induced transcriptional activation of host FUT genes associated with neo-expression of Ley in cytomegalovirus-infected and sialyl-Lex in varicella-zoster virus-infected diploid human cells
  • 2007
  • In: Glycobiology. - : Oxford University Press (OUP). - 1460-2423 .- 0959-6658. ; 17:4, s. 355-66
  • Journal article (peer-reviewed)abstract
    • Cell surface carbohydrate structures including sialyl-Lewis X (sLe(x)) and Lewis Y (Le(y)) are important ligands in normal and malignant tissues. The aim here was to determine the possible influence on the expression of such antigens by two viruses varicella-zoster virus (VZV) and cytomegalovirus (CMV) involved in persistent infections of humans. We found that infection of human diploid fibroblasts with both viruses resulted in transcriptional activation of several fucosyltransferase (FUT) genes that were either dormant or expressed at low levels in uninfected cells. Both viruses induced FUT3, FUT5, and FUT6, encoding alpha1,3- and/or alpha1,4-specific fucosyltransferases. CMV, but not VZV, induced transcription of FUT1 (encoding an alpha1,2-specific fucosyltransferase), FUT7, and FUT9. The changes in transcription of FUT genes were expectedly associated with expression of Le(y) in CMV-infected cells and sLe(x) in the VZV-infected fibroblasts although no expression of these antigens was observed in uninfected cells. One major explanation for this difference between CMV- and VZV-infected cells was that CMV, but not VZV, induced expression of FUT1, necessary for Le(y) expression. The induced carbohydrate antigens in CMV- and VZV-infected cells could be of significance for virus spread and possible escape from immune responses.
  •  
35.
  • Rembeck, Karolina, et al. (author)
  • Variants of the inosine triphosphate pyrophosphatase gene are associated with reduced relapse risk following treatment for HCV genotype 2/3.
  • 2014
  • In: Hepatology (Baltimore, Md.). - : Ovid Technologies (Wolters Kluwer Health). - 1527-3350 .- 0270-9139. ; 59:6, s. 2131-2139
  • Journal article (peer-reviewed)abstract
    • The present study evaluated the impact of variations in the inosine triphosphate pyrophosphatase (ITPase) gene (ITPA) on treatment outcome in patients with hepatitis C virus (HCV) genotype 2/3 infection receiving peginterferon-α2a and lower, conventional 800 mg daily dose of ribavirin. Previous studies using higher, weight-based ribavirin dosing report that patients carrying polymorphisms encoding reduced predicted ITPase activity show decreased risk of ribavirin-induced anemia but increased risk of thrombocytopenia, with no impact on elimination of virus. Three hundred fifty-four treatment naïve HCV genotype 2/3 infected patients, enrolled in a phase III trial (NORDynamIC), were genotyped for ITPA (rs1127354 and rs7270101). Homo- or heterozygosity at Ars1127354 or Crs7270101, entailing reduced ITPase activity, was observed in 37% of patients and was associated with increased likelihood of achieving sustained virological response (SVR) (P=0.0003 in univariate and multivariate analyses) accompanied by a reduced risk of relapse among treatment-adherent patients. The association between ITPA variants and SVR remained significant when patients were subdivided by the 12- and 24-week treatment duration arms, HCV genotype, fibrosis stage and IL28B genotype, and was not secondary to improved adherence to therapy or less pronounced anemia. Gene variants predicting reduced predicted ITPase activity also were associated with decreased risk of anemia (P<0.0001), increased risk of thrombocytopenia (P=0.007), and lower ribavirin concentrations (P=0.02). Conclusion: These findings demonstrate a novel ribavirin-like association between polymorphisms at ITPA and treatment efficacy in chronic hepatitis C mediated by reduced relapse risk. We hypothesize that patients (63%) being homozygous for both major alleles, leading to normal ITPase activity, may benefit more from the addition of ribavirin to present and future treatment regimens for HCV in spite of concomitant increased risk of anemia.
  •  
36.
  • Ringlander, Johan, et al. (author)
  • Recurrent and persistent infection with SARS-CoV-2-epidemiological data and case reports from Western Sweden, 2020
  • 2021
  • In: Infectious Diseases. - : Informa UK Limited. - 2374-4235 .- 2374-4243. ; 53:12, s. 900-907
  • Journal article (peer-reviewed)abstract
    • Background Reinfections with SARS-CoV-2 have been reported and most cases were classified as mild. Reports of persistent infection with SARS-CoV-2 are rare. Aim To investigate the frequency of recurrent and persistent infection with SARS-CoV-2. Methods Possible cases of reinfection and persistent infection were retrospectively identified in a database of 59,998 patients. Deep sequencing of SARS-CoV-2 genomes was performed. Results We report the first case of COVID-19 reinfection in Sweden and three cases of infection with persistence over several months. The rate of sequencing-verified reinfection was 0.02% (one patient out of 6014 patients testing positive during the period). Conclusions The reinfected patient had mild symptoms during the second episode, which might reflect partial immunity. The frequency of reinfection during the first wave of the pandemic in western Sweden was very low. Our results indicate that elderly with a putative reinfection more likely have persistent COVID-19.
  •  
37.
  • Robertson, Josefina, et al. (author)
  • Increased immune activation and signs of neuronal injury in HIV-negative people on preexposure prophylaxis.
  • 2021
  • In: AIDS (London, England). - 1473-5571 .- 0269-9370. ; 35:13, s. 2129-2136
  • Journal article (peer-reviewed)abstract
    • Persistent immune activation in the central nervous system and systemically are common in people living with HIV (PLHIV) despite antiretroviral therapy. It is not known whether this is generated by HIV replication or by other components such as coinfections and lifestyle-related factors.The aim of this study was to determine the importance of different factors; it is crucial to find well matched HIV-negative controls. In this context, HIV-negative persons on preexposure prophylaxis (PrEP) may constitute a suitable control group to PLHIV with similar lifestyle-related factors.Cerebrospinal fluid (CSF) and blood were collected from 40 HIV-negative persons on PrEP and 20 controls without PrEP. Biomarkers of immune activation, blood--brain barrier (BBB) integrity and neuronal injury were analysed.CSF and serum β2-microglobulin, serum neopterin and CSF neurofilament light protein were higher in persons on PrEP compared with controls. Furthermore, persons on PrEP had higher CSF/plasma albumin ratio, and matrix metalloproteinase-3 concentrations, indicating BBB dysfunction. Of persons on PrEP, 90% were cytomegalovirus (CMV)-positive compared to 65% of the controls. CMV-positive individuals as a group had higher levels of serum β2-microglobulin than CMV-negative individuals (P<0.05). Drug users had higher serum β2-microglobulin compared to nonusers (P<0.01).HIV-negative persons on PrEP had higher levels of biomarkers for immune activation, BBB impairment and neuronal injury, compared with volunteers without PrEP. Moreover, serum β2-microglobulin was higher in CMV-positive than in CMV-negative individuals and in drug users compared with nonusers. These findings are important to consider when analysing immune activation and CNS injury in PLHIV, and emphasize the importance of appropriate controls.
  •  
38.
  • Saguti, Fredy, et al. (author)
  • Surveillance of wastewater revealed peaks of SARS-CoV-2 preceding those of hospitalized patients with COVID-19.
  • 2021
  • In: Water research. - : Elsevier BV. - 1879-2448 .- 0043-1354. ; 189
  • Journal article (peer-reviewed)abstract
    • SARS-CoV-2 was discovered among humans in Wuhan, China in late 2019, and then spread rapidly, causing a global pandemic. The virus was found to be transmitted mainly by respiratory droplets from infected persons or by direct contact. It was also shown to be excreted in feces, why we investigated whether the virus could be detected in wastewater and if so, to which extent its levels reflects its spread in society. Samples of wastewater from the city of Gothenburg, and surrounding municipalities in Sweden were collected daily from mid-February until June 2020 at the Rya wastewater treatment plant. Flow proportional samples of wastewater were collected to ensure that comparable amounts were obtained for analysis. Daily samples were pooled into weekly samples. Virus was concentrated on a filter and analyzed by RT-qPCR. The amount of SARS-CoV-2 varied with peaks approximately every four week, preceding variations in number of newly hospitalized patients by 19-21 days. At that time virus testing for COVID-19 was limited to patients with severe symptoms. Local differences in viral spread was shown by analyzing weekly composite samples of wastewater from five sampling sites for four weeks. The highest amount of virus was found from the central, eastern, and northern parts of the city. SARS-CoV-2 was also found in the treated effluent wastewater from the WWTP discharged into the recipient, the Göta River, although with a reduction of 4-log10. The viral peaks with regular temporal intervals indicated that SARS-CoV-2 may have a cluster spread, probably reflecting that the majority of infected persons only spread the disease during a few days. Our results are important for both the planning of hospital care and to rapidly identify and intervene against local spread of the virus.
  •  
39.
  • Saguti, Fredy, et al. (author)
  • Surveillance of wastewater revealed peaks of SARS-CoV-2 preceding those of hospitalized patients with COVID-19
  • 2021
  • In: Water Research. - : Elsevier BV. - 0043-1354 .- 1879-2448. ; 189
  • Journal article (peer-reviewed)abstract
    • SARS-CoV-2 was discovered among humans in Wuhan, China in late 2019, and then spread rapidly, causing a global pandemic. The virus was found to be transmitted mainly by respiratory droplets from infected persons or by direct contact. It was also shown to be excreted in feces, why we investigated whether the virus could be detected in wastewater and if so, to which extent its levels reflects its spread in society. Samples of wastewater from the city of Gothenburg, and surrounding municipalities in Sweden were collected daily from mid-February until June 2020 at the Rya wastewater treatment plant. Flow proportional samples of wastewater were collected to ensure that comparable amounts were obtained for analysis. Daily samples were pooled into weekly samples. Virus was concentrated on a filter and analyzed by RT-qPCR. The amount of SARS-CoV-2 varied with peaks approximately every four week, preceding variations in number of newly hospitalized patients by 19-21 days. At that time virus testing for COVID-19 was limited to patients with severe symptoms. Local differences in viral spread was shown by analyzing weekly composite samples of wastewater from five sampling sites for four weeks. The highest amount of virus was found from the central, eastern, and northern parts of the city. SARS-CoV-2 was also found in the treated effluent wastewater from the WWTP discharged into the recipient, the Göta River, although with a reduction of 4-log10. The viral peaks with regular temporal intervals indicated that SARS-CoV-2 may have a cluster spread, probably reflecting that the majority of infected persons only spread the disease during a few days. Our results are important for both the planning of hospital care and to rapidly identify and intervene against local spread of the virus.
  •  
40.
  • Saguti, Fredy, et al. (author)
  • The UV Dose Used for Disinfection of Drinking Water in Sweden Inadequately Inactivates Enteric Virus with Double-Stranded Genomes
  • 2022
  • In: International Journal of Environmental Research and Public Health. - : MDPI AG. - 1660-4601 .- 1661-7827. ; 19:14
  • Journal article (peer-reviewed)abstract
    • Irradiation with ultraviolet light (UV) at 254 nm is effective in inactivating a wide range of human pathogens. In Sweden, a UV dose of 400 J/m(2) is often used for the treatment of drinking water. To investigate its effect on virus inactivation, enteric viruses with different genomic organizations were irradiated with three UV doses (400, 600, and 1000 J/m(2)), after which their viability on cell cultures was examined. Adenovirus type 2 (double-stranded DNA), simian rotavirus 11 (double-stranded RNA), and echovirus 30 (single-stranded RNA) were suspended in tap water and pumped into a laboratory-scale Aquada 1 UV reactor. Echovirus 30 was reduced by 3.6-log(10) by a UV dose of 400 J/m(2). Simian rotavirus 11 and adenovirus type 2 were more UV resistant with only 1-log(10) reduction at 400 J/m(2) and needed 600 J/m(2) for 2.9-log(10) and 3.1-log(10) reductions, respectively. There was no significant increase in the reduction of viral viability at higher UV doses, which may indicate the presence of UV-resistant viruses. These results show that higher UV doses than those usually used in Swedish drinking water treatment plants should be considered in combination with other barriers to disinfect the water when there is a risk of fecal contamination of the water.
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41.
  • Saguti, Fredy, et al. (author)
  • The Virucidal Effect of the Chlorination of Water at the Initial Phase of Disinfection May Be Underestimated If Contact Time Calculations Are Used
  • 2023
  • In: Pathogens. - 2076-0817. ; 12:10
  • Journal article (peer-reviewed)abstract
    • For the microbiological safety of drinking water, disinfection methods are used to remove or inactivate microorganisms. Chlorine and chlorine dioxide are often used as disinfectants in drinking water treatment plants (DWTPs). We investigated the effectiveness of these chemicals in inactivate echovirus 30 (E30), simian 11 rotavirus (RV SA11), and human adenovirus type 2 (HAdV2) in purified water from a DWTP. Within two minutes of contact, chlorine dioxide inactivated E30 by 4-log10, RV SA11 by 3-log10, and HAdV2 could not be detected, while chlorine reduced E30 by 3-log10, RV SA11 by 2-3log10, and HAdV2 by 3-4log10. However, viral genomes could be detected for up to 2 h using qPCR. The CT method, based on a combination of disinfectant concentration and contact time, during such a short initial phase, is problematic. The high concentrations of disinfectant needed to neutralize organic matter may have a strong immediate effect on virus viability. This may lead to the underestimation of disinfection and overdosing of disinfectants in water with organic contamination. These results are useful for the selection of disinfection systems for reuse of treated wastewater and in the risk assessment of water treatment processes using chlorine and chlorine dioxide.
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42.
  • Sharma, Tanuj, et al. (author)
  • Identifying novel inhibitors targeting Exportin-1 for the potential treatment of COVID-19
  • 2024
  • In: ARCHIVES OF MICROBIOLOGY. - 0302-8933 .- 1432-072X. ; 206:2
  • Journal article (peer-reviewed)abstract
    • The nuclear export protein 1 (XPO1) mediates the nucleocytoplasmic transport of proteins and ribonucleic acids (RNAs) and plays a prominent role in maintaining cellular homeostasis. XPO1 has emerged as a promising therapeutic approach to interfere with the lifecycle of many viruses. In our earlier study, we proved the inhibition of XPO1 as a therapeutic strategy for managing SARS-COV-2 and its variants. In this study, we have utilized pharmacophore-assisted computational methods to identify prominent XPO1 inhibitors. After several layers of screening, a few molecules were shortlisted for further experimental validation on the in vitro SARS-CoV-2 cell infection model. It was observed that these compounds reduced spike positivity, suggesting inhibition of SARS-COV-2 infection. The outcome of this study could be considered further for developing novel antiviral therapeutic strategies against SARS-CoV-2.
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43.
  • Waldenström, Jesper, 1985, et al. (author)
  • Absence of interferon-lambda 4 enhances spontaneous clearance of acute hepatitis C virus genotypes 1-3 infection
  • 2021
  • In: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 56:7
  • Journal article (peer-reviewed)abstract
    • Objectives Absence of a functional interferon-lambda 4 (IFN-lambda 4) gene (IFNL4) predicts spontaneous resolution of acute hepatitis C virus (HCV) infections in regions with a predominance of genotype 1, whereas variants of the inosine triphosphate pyrophosphatase (ITPase) gene (ITPA) entailing reduced activity associate with increased sustained virologic response rates following some therapeutic regimens. This study aimed at investigating the impact of IFNL4 on acute HCV genotype 2 or 3 infections, and whether ITPase activity influenced outcome. Materials and Methods Two hundred and seven people who injected drugs (PWID) with documented anti-HCV seroconversion, and 57 PWID with reinfection with HCV were analyzed regarding IFNL4 (rs368234815 and rs12979860) and ITPA (rs1127354 and rs7270101), and longitudinally followed regarding HCV RNA. Results The spontaneous clearance of HCV infection in anti-HCV seronegative PWID was enhanced when IFN-lambda 4 was absent (44% vs. 20% for IFNL4 TT/TTrs1368234815 and Delta G(rs1368234815) respectively, p < .001; OR 3.2) across genotypes 1-3. The proportion lacking IFN-lambda 4 was further increased following resolution of repeated re-exposure to HCV (74% among re-infected participants who had cleared at least two documented HCV infections). ITPA genetic variants did not independently impact on the outcome, but among males lacking IFN-lambda 4, reduced ITPase activity markedly augmented the likelihood of resolution (65% vs. 29% for <100% and 100% ITPase activity, p = .006). Conclusions Absence of IFN-lambda 4 entails an enhanced likelihood of spontaneous resolution both following primary acute infection and repeated re-exposure to HCV across genotypes 1-3. Among men lacking IFN-lambda 4, reduced ITPase activity improved outcome.
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44.
  • Waldenström, Jesper, 1985, et al. (author)
  • Randomized Trial Evaluating the Impact of Ribavirin Mono-Therapy and Double Dosing on Viral Kinetics, Ribavirin Pharmacokinetics and Anemia in Hepatitis C Virus Genotype 1 Infection
  • 2016
  • In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:5
  • Journal article (peer-reviewed)abstract
    • In this pilot study (RibaC), 58 hepatitis C virus (HCV) genotype 1 infected treatment-naive patients were randomized to (i) 2 weeks ribavirin double dosing concomitant with pegylated interferon-alpha (pegIFN-alpha), (ii) 4 weeks ribavirin mono-therapy prior to adding pegIFN-alpha, or (iii) standard-of-care (SOC) ribavirin dosing concurrent with pegIFN-alpha. Four weeks of ribavirin mono-therapy resulted in a mean 0.46 log(10) IU/mL HCV RNA reduction differentially regulated across IL28B genotypes (0.89 vs. 0.21 log(10) IU/mL for CC and CT/TT respectively; P = 0.006), increased likelihood of undetectable HCV RNA week 4 after initiating pegIFN-alpha and thus shortened treatment duration (P < 0.05), and decreased median IP-10 concentration from 550 to 345 pg/mL (P < 0.001). Both experimental strategies impacted on ribavirin concentrations, and high levels were achieved after one week of double dosing. However, by day 14, double dosing entailed a greater hemoglobin decline as compared to SOC (2.2 vs. 1.4 g/dL; P = 0.03). Conclusion: Ribavirin down-regulates IP-10, and may have an antiviral effect differently regulated across IL28B genotypes.
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45.
  • Waldenström, Jesper, 1985, et al. (author)
  • The relation of 25-hydroxy vitamin D concentrations to liver histopathology, seasonality and baseline characteristics in chronic hepatitis C virus genotype 2 or 3 infection
  • 2020
  • In: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 15:8
  • Journal article (peer-reviewed)abstract
    • Background and objectives The hydroxylation to 25-hydroxy vitamin D (25(OH)D) occurs in the liver and the impact of liver disease on vitamin D is unclear. This study evaluated the relationship between vitamin D concentrations and hepatic histopathology, seasonality and patient characteristics in well-characterized patients having undergone a liver biopsy. Method 25(OH)D was measuredpost-hocin pre-treatment serum from 331 North European patients with chronic HCV genotype 2 or 3 infection (NORDynamIC study). Liver biopsies were scored for fibrosis and inflammation according to the Ishak protocol, and graded for steatosis. Non-invasive markers of hepatic fibrosis as well as baseline viral and host characteristics, including genetic polymorphisms rs2228570, rs7975232, and rs10877012 were also evaluated. Results Mean 25(OH)D concentration was 59 +/- 23 nmol/L, with 41% having values <50 nmol/L and 6% were <30 nmol/L. 25(OH)D correlated with fibrosis (r = -0.10, p <= 0.05) in univariate but not in multivariate analyses. No association was observed between 25(OH)D and hepatic inflammation, but with steatosis in HCV genotype 2 infected patients. None of the genetic polymorphisms impacted on 25(OH)D levels or fibrosis. 25(OH)D levels were significantly inversely correlated to BMI (r = -0.19, p = 0.001), and was also associated with season and non-Caucasian ethnicity. Conclusion Fibrosis was not independently associated with 25(OH)D concentration and no association was seen with hepatic inflammation, but HCV genotype 2 infected patients with moderate-to-severe steatosis had lower 25(OH)D levels compared to those without steatosis. A high percentage had potential risk of 25(OH)D deficiency, and BMI, seasonality and ethnicity were independently associated with 25(OH)D as previously reported.
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46.
  • Wang, Hao, et al. (author)
  • Hepatitis E virus strains infecting Swedish domestic pigs are unique for each pig farm and remain in the farm for at least 2years.
  • 2019
  • In: Transboundary and emerging diseases. - : Hindawi Limited. - 1865-1682 .- 1865-1674. ; 66:3, s. 1314-1323
  • Journal article (peer-reviewed)abstract
    • Hepatitis E virus (HEV) genotype 3 (HEV3) is distributed globally and infects both humans and animals, mainly domestic pigs and wild boars, which are the major reservoirs. In this study, the prevalence of HEV among Swedish pigs was investigated by HEV RNA analysis in 363 faecal samples from 3-month-old piglets sampled twice (2013 and 2014) in 30 Swedish pig farms. Four different types of farms were investigated; organic, conventional closed (keeping the sow), satellites in a sow pool (conventional farms sharing sows) and conventional non-closed farms (purchasing gilts). More than two-thirds (77%) of the farms had HEV-infected pigs. HEV RNA was found in faeces from 79 pigs (22%). Partial ORF1 could be sequenced in 46 strains. Phylogenetic analysis revealed a unique HEV3 strain for each farm. Strains sampled more than a year apart from the same farm were closely related, indicating that the same HEV strain is present for several years on the farm. Despite that only 4% of the Swedish pig farms were investigated, two farms had strains similar to those from humans, another had strains similar to wild boar HEV. The uniqueness of strains from each farm indicates a possibility to identify a source of infection down to farm level. This knowledge may be used by the farms to investigate the effectiveness of good hygiene routines to reduce the amount of HEV and thus the infection risk in the farm, and for Swedish public health authorities to identify cases of HEV transmissions from consumption of uncooked pork.
  •  
47.
  • Wang, Hao, et al. (author)
  • Measures against COVID-19 affected the spread of human enteric viruses in a Swedish community, as found when monitoring wastewater
  • 2023
  • In: SCIENCE OF THE TOTAL ENVIRONMENT. - 0048-9697. ; 895
  • Journal article (peer-reviewed)abstract
    • The quantification of viral genomes in wastewater reflects the prevalence of viral infections within the community. Knowledge of how the spread of common enteric viruses in the community was affected by the Swedish COVID-19 interventions is limited. To investigate this, the weekly wastewater samples collected for monitoring SARS-CoV-2 throughout the COVID-19 pandemic at the Rya sewage treatment plant in Gothenburg were also analyzed for adenovirus, norovirus GII, astrovirus, and rotavirus. The amount of each viral genome was quantified by real-time-qPCR and compared with the quantity of these viral genomes in wastewater from 2017. The results showed that the winter seasonality of norovirus GII and rotavirus in wastewater observed in 2017 was interrupted shortly after the introduction of the COVID-19 interventions, and they remained at low level throughout the pandemic. The circulation pattern of astrovirus and adenovirus was less affected. When the COVID-19 restrictions were lifted in 2022, a dramatic increase was observed in the amount of norovirus GII, rotavirus, and adenovirus genomes in wastewater. The changes in abundance and seasonality of some viruses identified through wastewater monitoring were consistent with changes in the number of patients diagnosed with these viruses. These findings suggest that moderate intervention to prevent COVID19 significantly reduced the spread of some enteric viruses in the community. The results show that wastewater monitoring is a valuable tool for detecting the spread and outbreaks of viral infections that may cause gastroenteritis also when people do not seek medical help, such as during the COVID-19 pandemic.
  •  
48.
  • Wang, Hao, et al. (author)
  • The amount of SARS-CoV-2 RNA in wastewater relates to the development of the pandemic and its burden on the health system
  • 2022
  • In: iScience. - : Elsevier BV. - 2589-0042. ; 25:9
  • Journal article (peer-reviewed)abstract
    • Virus surveillance in wastewater can be a useful indicator of the development of the COVID-19 pandemic in communities. However, knowledge about how the amount of SARS-CoV-2 RNA in wastewater relates to different data on the burden on the health system is still limited. Herein, we monitored the amount of SARS-CoV-2 RNA and the spectrum of virus variants in weekly pooled wastewater samples for two years from mid-February 2020 and compared them with several clinical data. The two-year monitoring showed the weekly changes in the amount of viral RNA in wastewater preceded the hospital care needs for COVID-19 and the number of acute calls on adult acute respiratory distress by 1-2 weeks during the first three waves of COVID-19. Our study demonstrates that virus surveillance in wastewater can predict the development of a pandemic and its burden on the health system, regardless of society's test capacity and possibility of tracking infected cases.
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