| 1. |
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| 2. |
- Alkharaan, Hassan, et al.
(author)
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Persisting Salivary IgG Against SARS-CoV-2 at 9 Months After Mild COVID-19 : A Complementary Approach to Population Surveys
- 2021
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In: Journal of Infectious Diseases. - : Oxford University Press (OUP). - 0022-1899 .- 1537-6613. ; 224:3, s. 407-414
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Journal article (peer-reviewed)abstract
- Background. Declining humoral immunity in coronavirus disease 2019 (COVID-19) patients and possible reinfection have raised concern. Mucosal immunity, particularly salivary antibodies, may be short lived although long-term studies are lacking. Methods. Using a multiplex bead-based array platform, we investigated antibodies specific to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proteins in 256 saliva samples from convalescent patients 1-9 months after symptomatic COVID-19 (n = 74, cohort 1), undiagnosed individuals with self-reported questionnaires (n = 147, cohort 2), and individuals sampled prepandemic (n = 35, cohort 3). Results. Salivary IgG antibody responses in cohort 1 (mainly mild COVID-19) were detectable up to 9 months postrecovery, with high correlations between spike and nucleocapsid specificity. At 9 months, IgG remained in blood and saliva in most patients. Salivary IgA was rarely detected at this time point. In cohort 2, salivary IgG and IgA responses were significantly associated with recent history of COVID-19-like symptoms. Salivary IgG tolerated temperature and detergent pretreatments. Conclusions. Unlike SARS-CoV-2 salivary IgA that appeared short lived, specific saliva IgG appeared stable even after mild COVID-19, as for blood serology. This noninvasive saliva-based SARS-CoV-2 antibody test with home self-collection may be a complementary alternative to conventional blood serology.
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| 3. |
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| 4. |
- Brokaw, Alyssa, et al.
(author)
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A Recombinant Alpha-Like Protein Subunit Vaccine (GBS-NN) Provides Protection in Murine Models of Group B Streptococcus Infection
- 2022
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In: The Journal of infectious diseases. - : Oxford University Press (OUP). - 1537-6613 .- 0022-1899. ; 226:1, s. 177-187
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Journal article (peer-reviewed)abstract
- BACKGROUND: Group B Streptococcus (GBS) transmission during pregnancy causes preterm labor, stillbirths, fetal injury, or neonatal infections. Rates of adult infections are also rising. The GBS-NN vaccine, engineered by fusing N-terminal domains of GBS Alpha C and Rib proteins, is safe in healthy, nonpregnant women, but further assessment is needed for use during pregnancy. Here, we tested GBS-NN vaccine efficacy using mouse models that recapitulate human GBS infection outcomes. METHODS: Following administration of GBS-NN vaccine or adjuvant, antibody profiles were compared by ELISA. Vaccine efficacy was examined by comparing infection outcomes in GBS-NN vaccinated versus adjuvant controls during systemic and pregnancy-associated infections, and during intranasal infection of neonatal mice following maternal vaccination. RESULTS: Vaccinated mice had higher GBS-NN-specific IgG titers versus controls. These antibodies bound alpha C and Rib on GBS clinical isolates. Fewer GBS were recovered from systemically challenged vaccinated mice versus controls. Although vaccination did not eliminate GBS during ascending infection in pregnancy, vaccinated dams experienced fewer in utero fetal deaths. Additionally, maternal vaccination prolonged neonatal survival following intranasal GBS challenge. CONCLUSIONS: These findings demonstrate GBS-NN vaccine efficacy in murine systemic and perinatal GBS infections and suggest that maternal vaccination facilitates the transfer of protective antibodies to neonates.
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| 5. |
- Bucardo, Filemón, et al.
(author)
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Association of Genetic Polymorphisms in DC-SIGN, Toll-Like Receptor 3, and Tumor Necrosis Factor a Genes and the Lewis-Negative Phenotype With Chikungunya Infection and Disease in Nicaragua
- 2021
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In: Journal of Infectious Diseases. - : Oxford University Press. - 0022-1899 .- 1537-6613. ; 223:2, s. 278-286
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Journal article (peer-reviewed)abstract
- BackgroundChikungunya infections range from subclinical infection to debilitating arthralgia and to chronic inflammatory rheumatism. Tumor necrosis factor (TNF) α, DC-SIGN (dendritic cell–specific intercellular adhesion molecule 3–grabbing nonintegrin), Toll-like receptor (TLR) 3, and blood groups have been directly or indirectly implicated in the susceptibility and pathogenesis of chikungunya.MethodsTo test the hypothesis that polymorphisms in genes coding for these molecules determine clinical outcomes of chikungunya infection, a retrospective case-control study was performed in León, Nicaragua. The study included 132 case patients and 132 controls, matched for age, sex and neighborhood. Case patients had clinical symptoms of chikungunya, which was diagnosed by means of polymerase chain reaction. Controls were individuals not reporting abrupt presentation of clinical chikungunya-like symptoms. Polymorphisms were identified by TaqMan single-nucleotide polymorphism genotyping assays.ResultsAfter adjustment for sociodemographic risk factors, chikungunya disease was associated with polymorphism in DC-SIGN and TLR3 genes (odds ratios, 5.2 and 3.3, respectively), and TNF-α with reduced persistent joint pain (0.24). Persistent joint pain was also associated with age, female sex and other comorbid conditions. Most interestingly, the Lewis-negative phenotype was strongly associated with both symptomatic chikungunya and immunoglobulin G seropositivity (odds ratios, 2.7, and 3.3, respectively).ConclusionThis study identified polymorphisms in DC-SIGN, TLR3, and TNF-α genes as well as Lewis-negative phenotype as risk factors for chikungunya infection and disease progression.
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| 6. |
- Cunningham, Janet, et al.
(author)
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Antibody Responses to Severe Acute Respiratory Syndrome Coronavirus 2 in the Serum and Cerebrospinal Fluid of Patients With Coronavirus Disease 2019 and Neurological Symptoms
- 2022
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In: Journal of Infectious Diseases. - : Oxford University Press (OUP). - 0022-1899 .- 1537-6613. ; 225:6, s. 965-970
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Journal article (peer-reviewed)abstract
- Antibody responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in serum and cerebrospinal fluid (CSF) samples from 16 patients with coronavirus disease 2019 and neurological symptoms were assessed using 2 independent methods. Immunoglobulin G (IgG) specific for the virus spike protein was found in 81% of patients in serum and in 56% in CSF. SARS-CoV-2 IgG in CSF was observed in 2 patients with negative serological findings. Levels of IgG in both serum and CSF were associated with disease severity (P < .05). All patients with elevated markers of central nervous system damage in CSF also had CSF antibodies (P = .002), and CSF antibodies had the highest predictive value for neuronal damage markers of all tested clinical variables.
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| 7. |
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| 8. |
- Cunningham, Janet L, et al.
(author)
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Anti-SARS-CoV2 antibody responses in serum and cerebrospinal fluid of COVID-19 patients with neurological symptoms.
- 2022
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In: The Journal of infectious diseases. - : Oxford University Press (OUP). - 1537-6613 .- 0022-1899. ; 225:6, s. 965-970
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Journal article (peer-reviewed)abstract
- Antibody responses to SARS-CoV-2 in serum and CSF from 16 COVID-19 patients with neurological symptoms were assessed using two independent methods. IgG specific for the virus spike protein was found in 81% of cases in serum and in 56% in CSF. SARS-CoV-2 IgG in CSF was observed in two cases with negative serology. Levels of IgG in both serum and CSF were associated with disease severity (p<0.05). All patients with elevated markers of CNS damage in CSF also had CSF antibodies (p=0.002), and CSF antibodies had the highest predictive value for neuronal damage markers of all tested clinical variables.
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| 9. |
- Dettwiler, Ines, et al.
(author)
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TIDE Analysis of Cryptosporidium Infections by gp60 Typing Reveals Obscured Mixed Infections
- 2022
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In: Journal of Infectious Diseases. - : Oxford University Press (OUP). - 0022-1899 .- 1537-6613. ; 225:4, s. 686-695
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Journal article (peer-reviewed)abstract
- Background. Cryptosporidiosis is a parasitic disease associated with potentially fatal diarrhea. The most used method in Cryptosporidium subtyping is based on the glycoprotein gene gp60. Each infection can represent a parasite population, and it is important to investigate the influence on transmission and virulence, as well as any impact on public health investigations. However, an easy-to-use method for detection is lacking. Methods. Here we report on the use of the bioinformatic program TIDE for deconvolution of gp60 chromatograms. A combination of single oocyst analysis and cloning successfully confirmed the within-sample parasite population diversity. Retrospective sample analysis was conducted on archived chromatograms. Results. For Cryptosporidium parvum, 8.6% multistrain infections (13 of 152) obscured by currently used consensus base calling were detected. Importantly, we show that single oocysts can harbor a mixed population of sporozoites. We also identified a striking dominance of unappreciated polymerase stutter artefacts in all 218 chromatograms analyzed, challenging the uncritical use of gp60 typing. Conclusions. We demonstrate the value of a new, easy-to-use analytical procedure for critical characterization of C. parvum and Cryptosporidium hominis in epidemiological investigations, also applicable retrospectively. Our findings illuminate the hidden parasite diversity with important implications for tracing zoonotic and person-to-person transmissions.
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| 10. |
- Edfeldt, Gabriella, et al.
(author)
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Regular Use of Depot Medroxyprogesterone Acetate Causes Thinning of the Superficial Lining and Apical Distribution of Human Immunodeficiency Virus Target Cells in the Human Ectocervix
- 2022
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In: Journal of Infectious Diseases. - : Oxford University Press. - 0022-1899 .- 1537-6613. ; 225:7, s. 1151-1161
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Journal article (peer-reviewed)abstract
- BackgroundThe hormonal contraceptive depot medroxyprogesterone acetate (DMPA) may be associated with an increased risk of acquiring human immunodeficiency virus (HIV). We hypothesize that DMPA use influences the ectocervical tissue architecture and HIV target cell localization.MethodsQuantitative image analysis workflows were developed to assess ectocervical tissue samples collected from DMPA users and control subjects not using hormonal contraception.ResultsCompared to controls, the DMPA group exhibited a significantly thinner apical ectocervical epithelial layer and a higher proportion of CD4+CCR5+ cells with a more superficial location. This localization corresponded to an area with a nonintact E-cadherin net structure. CD4+Langerin+ cells were also more superficially located in the DMPA group, although fewer in number compared to the controls. Natural plasma progesterone levels did not correlate with any of these parameters, whereas estradiol levels were positively correlated with E-cadherin expression and a more basal location for HIV target cells of the control group.ConclusionsDMPA users have a less robust epithelial layer and a more apical distribution of HIV target cells in the human ectocervix, which could confer a higher risk of HIV infection. Our results highlight the importance of assessing intact genital tissue samples to gain insights into HIV susceptibility factors.
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| 11. |
- Gallagher, Laura A., et al.
(author)
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Impaired Alanine Transport or Exposure to D-Cycloserine Increases the Susceptibility of MRSA to beta-lactam Antibiotics
- 2020
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In: Journal of Infectious Diseases. - : OXFORD UNIV PRESS INC. - 0022-1899 .- 1537-6613. ; 221:6, s. 1006-1016
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Journal article (peer-reviewed)abstract
- Prolonging the clinical effectiveness of beta-lactams, which remain first-line antibiotics for many infections, is an important part of efforts to address antimicrobial resistance. We report here that inactivation of the predicted D-cycloserine (DCS) transporter gene cycA resensitized methicillin-resistant Staphylococcus aureus (MRSA) to beta-lactam antibiotics. The cycA mutation also resulted in hypersusceptibility to DCS, an alanine analogue antibiotic that inhibits alanine racemase and D-alanine ligase required for D-alanine incorporation into cell wall peptidoglycan. Alanine transport was impaired in the cycA mutant, and this correlated with increased susceptibility to oxacillin and DCS. The cycA mutation or exposure to DCS were both associated with the accumulation of muropeptides with tripeptide stems lacking the terminal D-ala-D-ala and reduced peptidoglycan cross-linking, prompting us to investigate synergism between beta-lactams and DCS. DCS resensitized MRSA to beta-lactams in vitro and significantly enhanced MRSA eradication by oxacillin in a mouse bacteremia model. These findings reveal alanine transport as a new therapeutic target to enhance the susceptibility of MRSA to beta-lactam antibiotics.
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| 12. |
- Haas, David W., et al.
(author)
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Pharmacogenetics of Between-Individual Variability in Plasma Clearance of Bedaquiline and Clofazimine in South Africa
- 2022
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In: Journal of Infectious Diseases. - : Oxford University Press. - 0022-1899 .- 1537-6613. ; 226:1, s. 147-156
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Journal article (peer-reviewed)abstract
- In a cohort of patients treated for drug-resistant tuberculosis in South Africa, CYP3A5*3was associated with slower plasma bedaquiline clearance. Different CYP3A5*3minor allele frequencies among populations may help explain the more rapid bedaquiline clearance previously reported with African ancestry.Background Plasma bedaquiline clearance is reportedly more rapid with African ancestry. Our objective was to determine whether genetic polymorphisms explained between-individual variability in plasma clearance of bedaquiline, its M2 metabolite, and clofazimine in a cohort of patients treated for drug-resistant tuberculosis in South Africa.Methods Plasma clearance was estimated with nonlinear mixed-effects modeling. Associations between pharmacogenetic polymorphisms, genome-wide polymorphisms, and variability in clearance were examined using linear regression models.Results Of 195 cohort participants, 140 were evaluable for genetic associations. Among 21 polymorphisms selected based on prior genome-wide significant associations with any drug, rs776746 (CYP3A5*3) was associated with slower clearance of bedaquiline (P = .0017) but not M2 (P = .25). CYP3A5*3 heterozygosity and homozygosity were associated with 15% and 30% slower bedaquiline clearance, respectively. The lowest P value for clofazimine clearance was with VKORC1 rs9923231 (P = .13). In genome-wide analyses, the lowest P values for clearance of bedaquiline and clofazimine were with RFX4 rs76345012 (P = 6.4 x 10(-7)) and CNTN5 rs75285763 (P = 2.9 x 10(-8)), respectively.Conclusions Among South Africans treated for drug-resistant tuberculosis, CYP3A5*3 was associated with slower bedaquiline clearance. Different CYP3A5*3 frequencies among populations may help explain the more rapid bedaquiline clearance reported in Africans. Associations with RFX4 and CNTN5 are likely by chance alone.
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| 13. |
- Hastie, Andrew, et al.
(author)
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Immunogenicity of the adjuvanted recombinant zoster vaccine : persistence and anamnestic response to additional doses administered 10 years after primary vaccination.
- 2020
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In: Journal of Infectious Diseases. - : Oxford University Press (OUP). - 0022-1899 .- 1537-6613. ; 224:12, s. 2025-2034
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Journal article (peer-reviewed)abstract
- BACKGROUND: The adjuvanted recombinant zoster vaccine (RZV) is highly immunogenic and efficacious in adults ≥50 years (Y) of age (YOA). We evaluated (1) long-term immunogenicity of an initial 2-dose RZV schedule by following-up adults vaccinated at ≥60 YOA and by modeling, and (2) immunogenicity of 2 additional doses administered 10Y post-initial vaccination.METHODS: Persistence of humoral and cell-mediated immune (CMI) responses to 2 initial RZV doses was assessed through 10Y post-initial vaccination, and modeled through 20Y using a Piecewise, Power law and Fraser model. Immunogenicity and safety of 2 additional RZV doses were also evaluated (NCT02735915).RESULTS: Seventy adults were enrolled. Ten years post-initial vaccination, humoral and CMI responses were ~6-fold and ~3.5-fold above pre-initial vaccination levels, respectively. Predicted immune persistence through 20Y post-initial vaccination was similar across the 3 models. Sixty-two participants (82.6±4.4 YOA) received at least 1 additional RZV dose. Strong anamnestic humoral and CMI responses were elicited by 1 additional dose, without further increases after a second additional dose.CONCLUSIONS: Immune responses to an initial 2-dose RZV course persisted for many years in older adults. Strong anamnestic immune responses can be induced by additional dosing 10Y after the initial 2-dose course.
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| 14. |
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| 15. |
- Hedin, Wilhelm, et al.
(author)
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A Rough Colony Morphology of Mycobacterium abscessus Is Associated With Cavitary Pulmonary Disease and Poor Clinical Outcome
- 2023
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In: Journal of Infectious Diseases. - : Oxford University Press. - 0022-1899 .- 1537-6613. ; 227:6, s. 820-827
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Journal article (peer-reviewed)abstract
- Background: The Mycobacterium abscessus complex (MABC) is a difficult to treat mycobacterium with two distinct morphologies: smooth and rough. As the clinical implications are unclear, we explored the morphology of MABC in relation to disease and outcome.Methods: We performed a retrospective multicenter cohort study including patients with confirmed MABC in Sweden, 2009-2020, with treatment outcome as the primary outcome. MABC colony morphology was determined by light microscopy on Middlebrook 7H10 agar plates.Results: Of the 71 MABC isolates, a defined morphology could be determined for 63 isolates, of which 40 were smooth (56%) and 23 were rough (32%). Immunosuppression, pulmonary disease, and cavitary lesion on chest radiographs were significantly associated with a rough isolate morphology. Participants with smooth isolates had more favorable treatment outcomes (12/14, 86%) compared to those with rough isolates (3/10, 30%). In an age-adjusted logistic regression, rough morphology of MABC was associated to lower odds of clinical cure compared to smooth morphology (adjusted odds ratio, 0.12; P = .049).Conclusions: Study participants with rough MABC colony morphology of isolates had a worse clinical outcome compared to those with smooth isolates. The biological mechanisms should be further characterized and colony morphology of MABC taken into account during clinical management.
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| 16. |
- Henningsson, Anna J., 1972-, et al.
(author)
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Genome-wide DNA Methylation Profiling in Lyme Neuroborreliosis Reveals Altered Methylation Patterns of HLA Genes
- 2024
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In: Journal of Infectious Diseases. - : OXFORD UNIV PRESS INC. - 0022-1899 .- 1537-6613. ; 229:4, s. 1209-1214
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Journal article (peer-reviewed)abstract
- Lyme neuroborreliosis (LNB) is a complex neuroinflammatory disorder caused by Borrelia burgdorferi, which is transmitted through tick bites. Epigenetic alterations, specifically DNA methylation (DNAm), could play a role in the host immune response during infection. In this study, we present the first genome-wide analysis of DNAm in peripheral blood mononuclear cells from patients with LNB and those without LNB. Using a network-based approach, we highlighted HLA genes at the core of these DNAm changes, which were found to be enriched in immune-related pathways. These findings shed light on the role of epigenetic modifications in the LNB pathogenesis that should be confirmed and further expanded upon in future studies. We present the first genome-wide analysis of DNA methylation in peripheral blood mononuclear cells from patients with and those without the tick-borne infection Lyme neuroborreliosis (LNB). Our findings show that LNB is associated with immune-related DNA methylation changes.
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| 17. |
- Hjort, Karin, et al.
(author)
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Dynamics of Extensive Drug Resistance Evolution of Mycobacterium tuberculosis in a Single Patient During 9 Years of Disease and Treatment
- 2020
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In: Journal of Infectious Diseases. - : Oxford University Press (OUP). - 0022-1899 .- 1537-6613. ; 225:6, s. 1011-1020
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Journal article (peer-reviewed)abstract
- Mycobacterium tuberculosis is one of the hardest to treat bacterial pathogens with a high capacity to develop antibiotic resistance by mutations. Here we have performed whole-genome sequencing of consecutive M. tuberculosis isolates obtained during 9 years from a patient with pulmonary tuberculosis. The infecting strain was isoniazid resistant and during treatment it stepwise accumulated resistance mutations to 8 additional antibiotics. Heteroresistance was common and subpopulations with up to 3 different resistance mutations to the same drug coexisted. Sweeps of different resistant clones dominated the population at different time points, always coupled to resistance mutations coinciding with changes in the treatment regimens. Resistance mutations were predominant and no hitch-hiking, compensatory, or virulence-increasing mutations were detected, showing that the dominant selection pressure was antibiotic treatment. The results highlight the dynamic nature of M. tuberculosis infection, population structure, and resistance evolution and the importance of rapid antibiotic susceptibility tests to battle this pathogen.
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| 18. |
- Holmgren, Jan, 1944
(author)
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Modern History of Cholera Vaccines and the Pivotal Role of icddr,b
- 2021
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In: Journal of Infectious Diseases. - : Oxford University Press (OUP). - 0022-1899 .- 1537-6613. ; 224
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Journal article (peer-reviewed)abstract
- The rapid spread of the seventh cholera pandemic over Asia in the 1960s led to several large field studies that revealed that the traditional injectable cholera vaccines had poor efficacy, which led the World Health Organization (WHO) in the 1970s to stop recommending cholera vaccination. At the same time, it stimulated research that has led to the development of the effective orally administered cholera vaccines (OCVs) that today are a cornerstone in WHO's strategy for Ending Cholera-A Global Roadmap to 2030. The first effective OCV, Dukoral, containing a mixture of inactivated Vibrio cholerae bacteria and cholera toxin B subunit, was licensed in 1991 and is, together with 2 similar inactivated whole-cell OCVs, Shanchol and Euvichol, currently WHO prequalified and recommended OCVs. This brief review is a personal account of the modern history of the development of these now universally recognized effective tools.
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| 19. |
- Horsburgh, BA, et al.
(author)
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Cellular Activation, Differentiation, and Proliferation Influence the Dynamics of Genetically Intact Proviruses Over Time
- 2022
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In: The Journal of infectious diseases. - : Oxford University Press (OUP). - 1537-6613 .- 0022-1899. ; 225:7, s. 1168-1178
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Journal article (peer-reviewed)abstract
- Human immunodeficiency virus (HIV) persists in cells despite antiretroviral therapy; however, the influence of cellular mechanisms such as activation, differentiation, and proliferation upon the distribution of proviruses over time is unclear. To address this, we used full-length sequencing to examine proviruses within memory CD4+ T-cell subsets longitudinally in 8 participants. Over time, the odds of identifying a provirus increased in effector and decreased in transitional memory cells. In all subsets, more activated (HLA-DR–expressing) cells contained a higher frequency of intact provirus, as did more differentiated cells such as transitional and effector memory subsets. The proportion of genetically identical proviruses increased over time, indicating that cellular proliferation was maintaining the persistent reservoir; however, the number of genetically identical proviral clusters in each subset was stable. As such, key biological processes of activation, differentiation, and proliferation influence the dynamics of the HIV reservoir and must be considered during the development of any immune intervention.
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| 20. |
- Hu, Zhicheng, et al.
(author)
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The impact of aging and TLR2 deficiency on the clinical outcomes of Staphylococcus aureus bacteremia.
- 2023
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In: The Journal of infectious diseases. - : Oxford University Press (OUP). - 0022-1899 .- 1537-6613. ; 228:3, s. 332-342
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Journal article (peer-reviewed)abstract
- Staphylococcus aureus (S. aureus) causes a broad range of infections. TLR2 senses the S. aureus lipoproteins in S. aureus infections. Aging raises the risk of infection. Our aim was to understand how aging and TLR2 impact the clinical outcomes of S. aureus bacteremia. Four groups of mice (Wild type/young, Wild type/old, TLR2-/-/young, and TLR2-/-/old) were intravenously infected with S. aureus, and the infection course was followed. Both TLR2 deficiency and aging enhanced the susceptibility to disease. Increased age was the main contributing factor to mortality and changes in spleen weight, whereas other clinical parameters such as weight loss and kidney abscess formation were more TLR2 dependent. Importantly, aging increased mortality without relying on TLR2. In vitro, both aging and TLR2 deficiency downregulated cytokine/chemokine production of immune cells with distinct patterns. In summary, we demonstrate that aging and TLR2 deficiency impair the immune response to S. aureus bacteremia in distinct ways.
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| 21. |
- Jalkanen, Pinja, et al.
(author)
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A Combination of N and S Antigens With IgA and IgG Measurement Strengthens the Accuracy of SARS-CoV-2 Serodiagnostics
- 2021
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In: Journal of Infectious Diseases. - : Oxford University Press. - 0022-1899 .- 1537-6613. ; 224:2, s. 218-228
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Journal article (peer-reviewed)abstract
- Background. Primary diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is based on detection of virus RNA in nasopharyngeal swab samples. In addition, analysis of humoral immunity against SARS-CoV-2 has an important role in viral diagnostics and seroprevalence estimates. Methods. We developed and optimized an enzyme immunoassays (EIA) using SARS-CoV-2 nucleoprotein (N), Si and receptor binding domain (RBD) of the viral spike protein, and N proteins from SARS, Middle East respiratory syndrome (MERS), and 4 low-pathogenic human CoVs. Neutralizing antibody activity was compared with SARS-CoV-2 IgG, IgA, and IgM EIA results. Results. The sensitivity of EIA for detecting immune response in COVID-19 patients (n = 101) was 77% in the acute phase and 100% in the convalescent phase of SARS-CoV-2 infection when N and RBD were used as antigens in IgG and IgA specific EIAs. SARS-CoV-2 infection significantly increased humoral immune responses against the 229E and NL63 N proteins. Si and RBD-based EIA results had a strong correlation with microneutralization test results. Conclusions. The data indicate a combination of SARS-CoV-2 Si or RBD and N proteins and analysis of IgG and IgA immunoglobulin classes in sera provide an excellent basis for specific and sensitive serological diagnostics of COVID-19.
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| 22. |
- Jiang, Wei, et al.
(author)
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Cerebrospinal fluid and plasma lipopolysaccharide (LPS) levels in HIV-1 infection and associations with inflammation, blood-brain barrier permeability and neuronal injury.
- 2021
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In: The Journal of infectious diseases. - : Oxford University Press (OUP). - 1537-6613 .- 0022-1899. ; 223:9, s. 1612-1620
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Journal article (peer-reviewed)abstract
- HIV infection is associated with increased systemic microbial translocation, neuro-inflammation and occasionally neuronal injury. Whether systemic LPS penetrates into the brain and contributes to neuro-inflammation remain unknown in HIV. Here, we measured plasma and cerebrospinal fluid (CSF) LPS levels along with biomarkers of neuro-inflammation (white blood cell counts and 40 soluble markers) and neurofilament light chain (NfL). Notably, CSF LPS was undetectable in all samples, including three HIV-infected individuals with dementia. Increased plasma LPS, neuro-inflammation, and blood-brain barrier (BBB) dysfunction were found in untreated HIV-infected individuals, but not in healthy or treated HIV-infected individuals. Plasma LPS levels were directly correlated with various markers of inflammation in both plasma and CSF, as well as with degree of BBB permeability but not with CSF NfL in HIV-infected subjects. These results suggest that the magnitude of microbial translocation associates with neuro-inflammation and BBB permeability in HIV without direct penetration into the central nervous system (CNS).
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| 23. |
- Joseph, S. B., et al.
(author)
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Biotypes of Central Nervous System Complications in People With Human Immunodeficiency Virus: Virology, Immunology, and Neuropathology
- 2023
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In: Journal of Infectious Diseases. - : Oxford University Press (OUP). - 0022-1899 .- 1537-6613. ; 227:SUPP1
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Journal article (peer-reviewed)abstract
- Despite viral suppression with antiretroviral therapy (ART), people with human immunodeficiency virus (HIV) continue to experience central nervous system (CNS) complications, primarily in the form of mild cognitive impairment and mental health disorders (eg, depression, anxiety, other neuropsychiatric problems). The multifactorial pathogenesis and heterogeneity of mechanisms likely underlying CNS complications must be addressed in the development of preventive interventions and effective treatments. The biotyping approach has previously been useful to define phenotypes of other CNS diseases based on underlying mechanisms and could be translated to the field of neuroHIV. The purpose of the Biotype Workshop series, and the Virology, Immunology and Neuropathology Working Group in particular, is to capitalize on current and new technologies and guide future research efforts using the wealth of available immunological, virologic, and neuropathological data collected from people with HIV on and off ART.
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| 24. |
- Kanberg, Nelly, et al.
(author)
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COVID-19 Recovery: Consistent Absence of Cerebrospinal Fluid Biomarker Abnormalities in Patients With Neurocognitive Post-COVID Complications.
- 2024
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In: The Journal of infectious diseases. - 1537-6613. ; 229:2, s. 493-501
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Journal article (peer-reviewed)abstract
- To investigate evidence of residual viral infection, intrathecal immune activation, central nervous system (CNS) injury, and humoral responses in cerebrospinal fluid (CSF) and plasma in patients recovering from coronavirus disease 2019 (COVID-19), with or without neurocognitive post-COVID condition (PCC).Thirty-one participants (25 with neurocognitive PCC) underwent clinical examination, lumbar puncture, and venipuncture ≥3 months after COVID-19 symptom onset. Healthy volunteers were included. CSF and plasma severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid and spike antigen (N-Ag, S-Ag), and CSF biomarkers of immune activation and neuronal injury were analyzed.SARS-CoV-2 N-Ag or S-Ag were undetectable in all samples and no participant had pleocytosis. We detected no significant differences in CSF and plasma cytokine concentrations, albumin ratio, IgG index, neopterin, β2M, or in CSF biomarkers of neuronal injury and astrocytic damage. Furthermore, principal component analysis (PCA1) analysis did not indicate any significant differences between the study groups in the marker sets cytokines, neuronal markers, or anti-cytokine autoantibodies.We found no evidence of ongoing viral replication, immune activation, or CNS injury in plasma or CSF in patients with neurocognitive PCC compared with COVID-19 controls or healthy volunteers, suggesting that neurocognitive PCC is a consequence of events suffered during acute COVID-19 rather than persistent viral CNS infection or residual CNS inflammation.
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| 25. |
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| 26. |
- Karlsson, Lovisa, et al.
(author)
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A DNA Methylation Signature From Buccal Swabs to Identify Tuberculosis Infection
- 2024
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In: Journal of Infectious Diseases. - : OXFORD UNIV PRESS INC. - 0022-1899 .- 1537-6613.
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Journal article (peer-reviewed)abstract
- Background Tuberculosis (TB) is among the largest infectious causes of death worldwide, and there is a need for a time- and resource-effective diagnostic methods. In this novel and exploratory study, we show the potential of using buccal swabs to collect human DNA and investigate the DNA methylation (DNAm) signatures as a diagnostic tool for TB.Methods Buccal swabs were collected from patients with pulmonary TB (n = 7), TB-exposed persons (n = 7), and controls (n = 9) in Sweden. Using Illumina MethylationEPIC array, the DNAm status was determined.Results We identified 5644 significant differentially methylated CpG sites between the patients and controls. Performing the analysis on a validation cohort of samples collected in Kenya and Peru (patients, n = 26; exposed, n = 9; control, n = 10) confirmed the DNAm signature. We identified a TB consensus disease module, significantly enriched in TB-associated genes. Last, we used machine learning to identify a panel of 7 CpG sites discriminative for TB and developed a TB classifier. In the validation cohort, the classifier performed with an area under the curve of 0.94, sensitivity of 0.92, and specificity of 1.Conclusions In summary, the result from this study shows clinical implications of using DNAm signatures from buccal swabs to explore new diagnostic strategies for TB. In this work we show that individuals with tuberculosis display distinct DNA methylation patterns in the buccal mucosa compared to healthy controls and tuberculosis-exposed individuals, showing the potential of using this DNA methylation signature as a diagnostic tool. Graphical Abstract
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| 27. |
- Kenyon, Chris, et al.
(author)
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Population-level antimicrobial consumption is associated with decreased antimicrobial susceptibility in Neisseria gonorrhoeae in 24 European countries : an ecological analysis
- 2020
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In: Journal of Infectious Diseases. - : Oxford University Press. - 0022-1899 .- 1537-6613. ; 221:7, s. 1107-1116
-
Journal article (peer-reviewed)abstract
- OBJECTIVES: There are substantial variations in Neisseria gonorrhoeae susceptibility to antimicrobials between different populations, and the reasons for this are largely unexplored. We aimed to assess if the population level consumption of antimicrobials is a contributory factor.METHODS: Using antimicrobial susceptibility data from 24 countries in the European Gonococcal Antimicrobial Surveillance Programme and antimicrobial consumption data from the IQVIA MIDAS database, we built mixed effects linear/logistic regression models with country-level cephalosporin, fluoroquinolone and macrolide consumption (standard doses/1000 population/year) as the explanatory variables (from 2009 to 2015) and 1-year lagged ceftriaxone, cefixime, azithromycin and ciprofloxacin geometric mean minimum inhibitory concentrations (MIC) as the outcome variables (2010 to 2016).RESULTS: Positive correlations were found between the consumption of cephalosporins and geometric mean MIC of ceftriaxone and cefixime (both P's <0.05). Fluoroquinolone consumption was positively associated with the prevalence of resistance to ciprofloxacin (P<0.05).CONCLUSIONS: Differences in population level consumption of particular antimicrobials may contribute to the variations in the level of antimicrobial resistance in N. gonorrhoeae in different settings. Further interventions to reduce misuse and overuse of antimicrobials in high-consumption populations and core-groups are required.
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| 28. |
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| 29. |
- Krzyzowska, Malgorzata, et al.
(author)
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Tofacitinib treatment in primary herpes simplex encephalitis interferes with anti-viral response.
- 2022
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In: The Journal of infectious diseases. - : Oxford University Press (OUP). - 1537-6613 .- 0022-1899. ; 225:9, s. 1545-1553
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Journal article (peer-reviewed)abstract
- Tofacitinib, a Janus kinase inhibitor, is a novel immunosuppressive drug for treatment of rheumatoid arthritis (RA). Herpes simplex virus type 1 (HSV-1) may cause encephalitis during primary infection or following reactivation from a latent state. Long-term tofacitinib treatment may increase the risk of this life-threatening condition. The aim of this study was to investigate the effect of tofacitinib on HSV-1 primary infection using a mouse model. Mice pre-treated with tofacitinib were intranasally infected with a clinical strain of HSV-1 and monitored for infection severity and anti-viral response. Tofacitinib treatment of HSV-1 primary infection resulted in increased viral loads and worsened clinical outcome. Furthermore, tofacitinib promoted M2 anti-inflammatory phenotype of microglia and infiltrating monocytes as well as inhibited production of inflammatory and antiviral cytokines by macrophages in vitro. Our findings show that treatment with tofacitinib increases severity of HSE in mice, by impairing anti-viral response induced by monocytes and microglia.
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| 30. |
- Laake, Ida, et al.
(author)
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Concurrent Infection With Multiple Human Papillomavirus Types Among Unvaccinated and Vaccinated 17-Year-Old Norwegian Girls
- 2020
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In: Journal of Infectious Diseases. - : Oxford University Press (OUP). - 0022-1899 .- 1537-6613. ; 226:4, s. 625-633
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Journal article (peer-reviewed)abstract
- Background: Whether type-specific human papillomavirus (HPV) infection influences the risk of acquiring infections with other HPV types is unclear. We studied concurrent HPV infections in 17-year-old girls from 2 birth cohorts; the first vaccine-eligible cohort in Norway and a prevaccination cohort.Methods: Urine samples were collected and tested for 37 HPV genotypes. This study was restricted to unvaccinated girls from the prevaccination cohort (n = 5245) and vaccinated girls from the vaccine-eligible cohort (n = 4904). Risk of HPV infection was modelled using mixed-effect logistic regression. Expected frequencies of concurrent infection with each pairwise combination of the vaccine types and high-risk types (6/11/16/18/31/33/35/39/45/51/52/56/58/59) were compared to observed frequencies.Results: Infection with multiple HPV types was more common among unvaccinated girls than vaccinated girls (9.2% vs 3.7%). HPV33 and HPV51 was the only HPV pair that was detected together more often than expected among both unvaccinated (P = .002) and vaccinated girls (P < .001). No HPV pairs were observed significantly less often than expected.Conclusions: HPV33 and HPV51 tended to be involved in coinfection among both unvaccinated and vaccinated girls. The introduction of HPV vaccination does not seem to have had an effect on the tendency of specific HPV types to cluster together.
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| 31. |
- Liang, Frank, et al.
(author)
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Recurrent Herpes Zoster Ophthalmicus in a Patient With a Novel Toll-Like Receptor 3 Variant Linked to Compromised Activation Capacity in Fibroblasts
- 2020
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In: JOURNAL OF INFECTIOUS DISEASES. - : Oxford University Press (OUP). - 0022-1899 .- 1537-6613. ; 221:8, s. 1295-1303
-
Journal article (peer-reviewed)abstract
- Background. Herpes zoster ophthalmicus occurs primarily in elderly or immunocompromised individuals after reactivation of varicella zoster virus (VZV). Recurrences of zoster ophthalmicus are uncommon because the reactivation efficiently boosts anti-VZV immunity. A 28-year-old female presented to our clinic with a history of multiple recurrences of zoster ophthalmicus. Methods. Whole-exome sequencing (WES), analyses of VZV T-cell immunity, and pathogen recognition receptor function in primary antigen-presenting cells (APCs) and fibroblasts were performed. Results. Normal VZV-specific T-cell immunity and antibody response were detected. Whole-exome sequencing identified a heterozygous nonsynonymous variant (c.2324C > T) in the Toll-like receptor 3 (TLR3) gene resulting in formation of a premature stop-codon. This alteration could potentially undermine TLR3 signaling in a dominant-negative fashion. Therefore, we investigated TLR3 signaling responses in APCs and fibroblasts from the patient. The APCs responded efficiently to stimulation with TLR3 ligands, whereas the responses from the fibroblasts were compromised. Conclusions. We report a novel TLR3 variant associated with recurrent zoster ophthalmicus. Toll-like receptor 3 responses that were unaffected in APCs but diminished in fibroblasts are in line with previous reports linking TLR3 deficiency with herpes simplex virus encephalitis. Mechanisms involving compromised viral sensing in infected cells may thus be central to the described immunodeficiency.
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| 32. |
- Maravelia, Panagiota, et al.
(author)
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Blocking entry of hepatitis B and D viruses to hepatocytes as a novel immunotherapy for treating chronic infections
- 2021
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In: Journal of Infectious Diseases. - : Oxford University Press. - 0022-1899 .- 1537-6613. ; 223:1, s. 128-138
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Chronic hepatitis B and D virus (HBV/HDV) infections can cause cancer. Current HBV therapy using nucleoside analogues (NAs) is life-long and reduces but does not eliminate the risk of cancer. A hallmark of chronic hepatitis B is a dysfunctional HBV-specific T cell response. We therefore designed an immunotherapy driven by naïve healthy T cells specific for the HDV antigen (HDAg) to bypass the need for HBV-specific T cells in order to prime PreS1-specific T cells and PreS1 antibodies blocking HBV entry.METHODS: Ten combinations of PreS1 and/or HDAg sequences were evaluated for induction of PreS1 antibodies and HBV- and HDV- specific T cells in vitro and in vivo. Neutralization of HBV by PreS1-specific murine and rabbit antibodies was evaluated in cell culture, and rabbit anti-PreS1 were tested for neutralization of HBV in mice repopulated with human hepatocytes.RESULTS: The best vaccine candidate induced T cells to PreS1 and HDAg, and PreS1 antibodies blocking HBV entry in vitro. Importantly, adoptive transfer of PreS1 antibodies prevented, or modulated, HBV infection after a subsequent challenge in humanized mice.CONCLUSION: We here describe a novel immunotherapy for chronic HBV/HDV that targets viral entry to complement NAs and coming therapies inhibiting viral maturation.
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| 33. |
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| 34. |
- Mudde, Saskia E., et al.
(author)
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Predictive Modeling to Study the Treatment-Shortening Potential of Novel Tuberculosis Drug Regimens, Toward Bundling of Preclinical Data
- 2022
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In: Journal of Infectious Diseases. - : Oxford University Press. - 0022-1899 .- 1537-6613. ; 225:11, s. 1876-1885
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Journal article (peer-reviewed)abstract
- Background Given the persistently high global burden of tuberculosis, effective and shorter treatment options are needed. We explored the relationship between relapse and treatment length as well as interregimen differences for 2 novel antituberculosis drug regimens using a mouse model of tuberculosis infection and mathematical modeling. Methods Mycobacterium tuberculosis-infected mice were treated for up to 13 weeks with bedaquiline and pretomanid combined with moxifloxacin and pyrazinamide (BPaMZ) or linezolid (BPaL). Cure rates were evaluated 12 weeks after treatment completion. The standard regimen of isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE) was evaluated as a comparator. Results Six weeks of BPaMZ was sufficient to achieve cure in all mice. In contrast, 13 weeks of BPaL and 24 weeks of HRZE did not achieve 100% cure rates. Based on mathematical model predictions, 95% probability of cure was predicted to occur at 1.6, 4.3, and 7.9 months for BPaMZ, BPaL, and HRZE, respectively. Conclusion This study provides additional evidence for the treatment-shortening capacity of BPaMZ over BPaL and HRZE. To optimally use preclinical data for predicting clinical outcomes, and to overcome the limitations that hamper such extrapolation, we advocate bundling of available published preclinical data into mathematical models. By combining the evaluation of treatment efficacy of anti-tuberculosis drug regimens in a mouse tuberculosis infection model with mathematical modeling, it was found that BPaMZ had a higher treatment-shortening potential than BPaL, compared to the standard HRZE regimen.
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| 35. |
- Muhr, LSA, et al.
(author)
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Head-to-Head Comparison of Bi- and Nonavalent Human Papillomavirus Vaccine-Induced Antibody Responses
- 2022
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In: The Journal of infectious diseases. - : Oxford University Press (OUP). - 1537-6613 .- 0022-1899. ; 226:7, s. 1195-1199
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Journal article (peer-reviewed)abstract
- For head-to-head comparison of human papillomavirus (HPV) antibody levels induced by different vaccines, 25-year-old vaccine-naive women were given either the bivalent (n = 188) or the nonavalent HPV vaccine (n = 184). Six months after vaccination antibodies against pseudovirions from 17 different HPV types (HPV6/11/16/18/31/33/35/39/45/51/52/56/58/59/66/68/73) were measured. Antibodies against HPV16/18 were higher after bivalent HPV vaccination (mean international units [IU] 1140.1 and 170.5 for HPV16 and 18, respectively) than after nonavalent vaccination (265.1 and 22.3 IUs, respectively). The bivalent vaccine commonly induced antibodies against the nonvaccine HPV types 31/33/35/45 or 58. The nonavalent vaccine induced higher antibodies against HPV6/11/31/33/45/52/58 and 35.
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| 36. |
- Muvva, Jagadeeswara Rao, et al.
(author)
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Immunomodulatory Agents Combat Multidrug-Resistant Tuberculosis by Improving Antimicrobial Immunity
- 2021
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In: Journal of Infectious Diseases. - : Oxford University Press. - 0022-1899 .- 1537-6613. ; 224:2, s. 332-344
-
Journal article (peer-reviewed)abstract
- Background. Multidrug-resistant (MDR) tuberculosis has low treatment success rates, and new treatment strategies are needed. We explored whether treatment with active vitamin D-3 (vitD) and phenylbutyrate (PBA) could improve conventional chemotherapy by enhancing immune-mediated eradication of Mycobacterium tuberculosis. Methods. A clinically relevant model was used consisting of human macrophages infected with M. tuberculosis isolates (n = 15) with different antibiotic resistance profiles. The antimicrobial effect of vitD+PBA, was tested together with rifampicin or isoniazid. Methods included colony-forming units (intracellular bacterial growth), messenger RNA expression analyses (LL-37, beta-defensin, nitric oxide synthase, and dual oxidase 2), RNA interference (LL-37-silencing in primary macrophages), and Western blot analysis and confocal microscopy (LL-37 and LC3 protein expression). Results. VitD+PBA inhibited growth of clinical MDR tuberculosis strains in human macrophages and strengthened intracellular growth inhibition of rifampicin and isoniazid via induction of the antimicrobial peptide LL-37 and I,C3-dependent autophagy. Gene silencing of LL-37 expression enhanced MDR tuberculosis growth in vitD+PBA-treated macrophages. Me combination of vitD+PBA and isoniazid were as effective in reducing intracellular MDR tuberculosis growth as a >125-fold higher dose of isoniazid alone, suggesting potent additive effects of vitD+PBA with isoniazid. Conclusions. Immunomodulatory agents that trigger multiple immune pathways can strengthen standard MDR tuberculosis treatment and contribute to next-generation individualized treatment options for patients with difficult-to-treat pulmonary tuberculosis.
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| 37. |
- Nilchian, A, et al.
(author)
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Induction of the Coxsackievirus and Adenovirus Receptor in Macrophages During the Formation of Atherosclerotic Plaques
- 2020
-
In: The Journal of infectious diseases. - : Oxford University Press (OUP). - 1537-6613 .- 0022-1899. ; 222:12, s. 2041-2051
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Journal article (peer-reviewed)abstract
- Multiple viruses are implicated in atherosclerosis, but the mechanisms by which they infect cells and contribute to plaque formation in arterial walls are not well understood. Based on reports showing the presence of enterovirus in atherosclerotic plaques we hypothesized that the coxsackievirus and adenovirus receptor (CXADR/CAR), although absent in normal arteries, could be induced during plaque formation. Large-scale microarray and mass spectrometric analyses revealed significant up-regulation of CXADR messenger RNA and protein levels in plaque-invested carotid arteries compared with control arteries. Macrophages were identified as a previously unknown cellular source of CXADR in human plaques and plaques from Ldr−/−Apob100/100 mice. CXADR was specifically associated with M1-polarized macrophages and foam cells and was experimentally induced during macrophage differentiation. Furthermore, it was significantly correlated with receptors for other viruses linked to atherosclerosis. The results show that CXADR is induced in macrophages during plaque formation, suggesting a mechanism by which enterovirus infect cells in atherosclerotic plaques.
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| 38. |
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| 39. |
- Paavonen, Jorma, et al.
(author)
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Chlamydia trachomatis, Pelvic Inflammatory Disease, and Epithelial Ovarian Cancer
- 2021
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In: Journal of Infectious Diseases. - : Oxford University Press. - 0022-1899 .- 1537-6613. ; 224:Suppl 2, s. S121-S127
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Journal article (peer-reviewed)abstract
- Epidemiologic, clinical, molecular and translational research findings support an interrelationship between Chlamydia trachomatis, pelvic inflammatory disease (PID), and epithelial ovarian cancer (EOC). Overall, the link between C. trachomatis, PID, and EOC seems to be relatively weak, although nondifferential misclassification bias may have attenuated the results. The predominant tubal origin of EOC and the role of chronic inflammation in tumorigenesis suggest that the association is biologically plausible. Thus, C. trachomatis and PID may represent potential risk factors or risk markers for EOC. However, many steps in this chain of events are still poorly understood and need to be addressed in future studies. Research gaps include time of exposure in relation to the long-term consequences and lag time to EOC. Data of differential risk for EOC between chlamydial and nonchlamydial PID is also needed. Another major research gap has been the absence of high-performance biomarkers for C. trachomatis, PID, and EOC, as well as EOC precursors. Biomarkers for C. trachomatis and PID leading to increased risk of EOC should be developed. If the association is confirmed, C. trachomatis and PID prevention efforts may play a role in reducing the burden of EOC.
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| 40. |
- Pieterman, Elise D., et al.
(author)
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Superior Efficacy of a Bedaquiline, Delamanid, and Linezolid Combination Regimen in a Mouse Tuberculosis Model
- 2021
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In: Journal of Infectious Diseases. - : Oxford University Press. - 0022-1899 .- 1537-6613. ; 224:6, s. 1039-1047
-
Journal article (peer-reviewed)abstract
- Background: The treatment success rate of drug-resistant (DR) tuberculosis is alarmingly low. Therefore, more effective and less complex regimens are urgently required.Methods: We compared the efficacy of an all oral DR tuberculosis drug regimen consisting of bedaquiline (25 mg/kg), delamanid (2.5 mg/kg), and linezolid (100 mg/kg) (BDL) on the mycobacterial load in the lungs and spleen of tuberculosis-infected mice during a treatment period of 24 weeks. This treatment was compared with the standard regimen of isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE). Relapse was assessed 12 weeks after treatment. Two logistic regression models were developed to compare the efficacy of both regimens.Results: Culture negativity in the lungs was achieved at 8 and 20 weeks of treatment with BDL and HRZE, respectively. After 14 weeks of treatment only 1 mouse had relapse in the BDL group, while in the H RZE group relapse was still observed at 24 weeks of treatment. Predictions from the final mathematical models showed that a 95% cure rate was reached after 20.5 and 28.5 weeks of treatment with BDL and HRZE, respectively.Conclusion: The BDL regimen was observed to be more effective than HRZE and could be a valuable option for the treatment of DR tuberculosis.
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| 41. |
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| 42. |
- Reyes, Yaoska, et al.
(author)
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Nonsecretor Phenotype Is Associated With Less Risk of Rotavirus-Associated Acute Gastroenteritis in a Vaccinated Nicaraguan Birth Cohort
- 2023
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In: Journal of Infectious Diseases. - : OXFORD UNIV PRESS INC. - 0022-1899 .- 1537-6613. ; 228:12, s. 1739-1747
-
Journal article (peer-reviewed)abstract
- Background Histo-blood group antigens (HBGAs) have been associated with rotavirus vaccine take; but the effect of these HBGAs on rotavirus incidence and risk remains poorly explored in vaccinated populations. Methods Rotavirus-associated acute gastroenteritis (AGE) was assessed in 444 Nicaraguan children followed from birth until 3 years of age. AGE episodes were tested for rotavirus by reverse-transcription quantitative polymerase chain reaction, and saliva or blood was used to determine HBGA phenotypes. Cox proportional hazards models were used to estimate the relative hazard of rotavirus AGE by HBGA phenotypes. Results Rotavirus was detected in 109 (7%) stool samples from 1689 AGE episodes over 36 months of observation between June 2017 and July 2021. Forty-six samples were successfully genotyped. Of these, 15 (35%) were rotavirus vaccine strain G1P[8], followed by G8P[8] or G8P[nt] (11 [24%]) and equine-like G3P[8] (11 [24%]). The overall incidence of rotavirus-associated AGE was 9.2 per 100 child-years, and was significantly higher in secretor than nonsecretor children (9.8 vs 3.5/100 child-years, P = .002). Conclusions The nonsecretor phenotype was associated with decreased risk of clinical rotavirus vaccine failure in a vaccinated Nicaraguan birth cohort. These results show the importance of secretor status on rotavirus risk, even in vaccinated children. Overall incidence of rotavirus-associated AGE in a vaccinated Nicaraguan birth cohort was 9.2/100 child-years. Nonsecretor children had less risk of symptomatic rotavirus infection. These results are important in the context of monitoring effectiveness of rotavirus vaccine trough birth cohort studies.
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| 43. |
- Reyes, Yaoska, et al.
(author)
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Secretor Status Strongly Influences the Incidence of Symptomatic Norovirus Infection in a Genotype-Dependent Manner in a Nicaraguan Birth Cohort
- 2022
-
In: Journal of Infectious Diseases. - : OXFORD UNIV PRESS INC. - 0022-1899 .- 1537-6613. ; 225:1, s. 105-115
-
Journal article (peer-reviewed)abstract
- Background. The role of histo-blood group on the burden and severity of norovirus gastroenteritis in young infants has not been well documented. Methods. Norovirus gastroenteritis was assessed in 443 Nicaraguan children followed from birth until 3 years of age. Stool samples were tested for norovirus by reverse-transcription quantitative polymerase chain reaction (RT-qPCR), and histo-blood group antigens (HBGAs) were determined by phenotyping of saliva and blood. Hazard ratios and predictors of norovirus acute gastroenteritis (AGE) outcome stratified by HBGA were estimated using Cox proportional hazards models. Results. Of 1353 AGE episodes experienced by children, 229 (17%) tested positive for norovirus with an overall incidence of 21.9/100 child-years. Secretor children were infected as early as 2 months of age and had a higher incidence of norovirus GII compared to nonsecretor children (15.4 vs 4.1/100 child-years, P = .006). Furthermore, all GII.4 AGE episodes occurred in secretor children. Children infected with GI (adjusted odds ratio [aOR], 0.09 [95% confidence interval {CI}, .02-.33]) or non-GII.4 viruses (aOR, 0.2 [95% CI, .07-.6]) were less likely to have severe AGE compared to GII.4-infected children. Conclusions. Secretor status in children strongly influences the incidence of symptomatic norovirus infection in a genogroup or genotype-dependent manner and provides evidence that clinical severity in children depends on norovirus genotypes.
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| 44. |
- Ringlander, Johan, et al.
(author)
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Enrichment Reveals Extensive Integration of Hepatitis B Virus DNA in Hepatitis Delta Virus-Infected Patients
- 2024
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In: JOURNAL OF INFECTIOUS DISEASES. - 0022-1899 .- 1537-6613.
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Journal article (peer-reviewed)abstract
- Background. Hepatitis B virus (HBV) DNA may become integrated into the human genome of infected human hepatocytes. Expression of integrations can produce the surface antigen (HBsAg) that is required for synthesis of hepatitis D virus (HDV) particles and the abundant subviral particles in the blood of HBV- and HDV-infected subjects. Knowledge about the extent and variation of HBV integrations and impact on chronic HDV is still limited. Methods. We investigated 50 pieces of liver explant tissue from 5 patients with hepatitis D-induced cirrhosis, using a deep-sequencing strategy targeting HBV RNA. Results. We found that integrations were abundant and highly expressed, with large variation in the number of integration-derived (HBV/human chimeric) reads, both between and within patients. The median number of unique integrations for each patient correlated with serum levels of HBsAg. However, most of the HBV reads represented a few predominant integrations. Conclusions. The results suggest that HBV DNA integrates in a large proportion of hepatocytes, and that the HBsAg output from these integrations vary >100-fold depending on clone size and expression rate. A small proportion of the integrations seems to determine the serum levels of HBsAg and HDV RNA in HBV/HDV coinfected patients with liver cirrhosis.
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| 45. |
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| 46. |
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| 47. |
- Rydell, Gustaf E, et al.
(author)
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Abundance of non-circular intrahepatic hepatitis B virus DNA may reflect frequent integration into human DNA in chronically infected patients.
- 2022
-
In: The Journal of infectious diseases. - : Oxford University Press (OUP). - 1537-6613 .- 0022-1899. ; 225:11, s. 1982-1990
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Journal article (peer-reviewed)abstract
- Hepatitis B virus (HBV) integration has implications for cancer development and surface antigen (HBsAg) production, but methods to quantify integrations are lacking. The aim of this study was to develop a digital PCR (ddPCR) assay discriminating between circular and integrated HBV DNA, and to relate the distribution between the two forms to other HBV markers.ddPCR comprising primers spanning the typical linearization breakpoint in the HBV genome allowed for quantification of the absolute copy numbers of total and circular HBV DNA, and calculation of linear HBV DNA.Analysis of 70 liver biopsies from patients with chronic HBV infection revealed that the fraction of linear HBV DNA, which includes integrations, was higher in HBeAg-negative patients than HBeAg-positive. The ratio between HBsAg and HBV DNA levels in serum correlated with the intrahepatic proportion of linear HBV DNA. Furthermore, ddPCR experiments on serum samples and experiments with nuclease indicated the contribution of encapsidated double-stranded linear DNA and replication intermediates to be limited.The degree of integration of intrahepatic HBV DNA in the HBeAg-negative stage may be higher than previously anticipated, and integrated DNA may explain the persistence of high HBsAg serum levels in patients with low HBV DNA levels.
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| 48. |
- Rydell, Gustaf E, et al.
(author)
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Quantification of viral RNA in multiple pieces of explant liver tissue shows distinct focal differences of hepatitis B infection.
- 2022
-
In: The Journal of infectious diseases. - : Oxford University Press (OUP). - 1537-6613 .- 0022-1899. ; 226:6, s. 1036-1040
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Journal article (peer-reviewed)abstract
- Hepatitis B virus (HBV) DNA and RNA were quantified by digital PCR assays in 20-30 tissue pieces from each of four liver explants with cirrhosis caused by HBV. The within-patient variability of HBV RNA levels between pieces was up to thousand-fold. Core RNA and S RNA levels were similar and correlated strongly when replication was high, supporting transcription from cccDNA. By contrast, enhanced expression of S RNA relative to cccDNA and core RNA in patients with medium-high or low replication supports that HBV surface antigen (HBsAg) can be expressed mainly from integrated HBV DNA in such patients.
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| 49. |
- Schmedes, Clare M., et al.
(author)
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Circulating extracellular vesicle tissue factor activity during orthohantavirus infection is associated with intravascular coagulation
- 2020
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In: Journal of Infectious Diseases. - : Oxford University Press. - 0022-1899 .- 1537-6613. ; 222:8, s. 1392-1399
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Journal article (peer-reviewed)abstract
- BACKGROUND: Puumala (PUUV) orthohantavirus causes hemorrhagic fever with renal syndrome (HFRS). HFRS patients have an activated coagulation system with increased risk of disseminated intravascular coagulation (DIC) and venous thromboembolism (VTE). The aim of the study was to determine if circulating extracellular vesicle tissue factor (EVTF) activity levels associates with DIC and VTE (grouped as intravascular coagulation) in HFRS patients.METHODS: Longitudinal samples were collected from 88 HFRS patients. Patients were stratified into groups of those with intravascular coagulation (n=27) and those who did not (n=61). We measured levels of circulating EVTF activity, fibrinogen, activated partial prothrombin time, prothrombin time international normalized ratio, D-dimer, tissue plasminogen activator (tPA), plasminogen activator inhibitor 1 (PAI-1) and platelets.RESULTS: Plasma EVTF activity was transiently increased during HFRS. Levels of EVTF activity significantly associated with plasma tPA and PAI-1, suggesting endothelial cells as a potential source. Patients with intravascular coagulation had significantly higher peak EVTF activity levels compared to those who did not. The peak EVTF activity value predicting intravascular coagulation was 0.51 ng/L with 63% sensitivity and 61% specificity with AUC 0.63 (95% CI 0.51 - 0.76), p-value 0.046.CONCLUSIONS: Increased circulating EVTF activity during HFRS is associated with intravascular coagulation.
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| 50. |
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