| 1. |
- Bucardo, Filemon, et al.
(author)
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Pediatric norovirus diarrhea in Nicaragua
- 2008
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In: Journal of Clinical Microbiology. - 0095-1137 .- 1098-660X. ; 46:8, s. 2573-2580
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Journal article (peer-reviewed)abstract
- Information about norovirus (NoV) infections in Central America is limited. Through a passive community and hospital pediatric diarrhea surveillance program, a total of 542 stool samples were collected between March 2005 and February 2006 in León, Nicaragua. NoV was detected in 12% (65/542) of the children; of these, 11% (45/409) were in the community and 15% (20/133) were in the hospital, with most strains (88%) belonging to genogroup II. NoV infections were age and gender associated, with children of <2 years of age (P < 0.05) and girls (P < 0.05) being most affected. Breast-feeding did not reduce the number of NoV infections. An important proportion (57%) of NoV-infected children were coinfected with diarrheagenic Escherichia coli. A significant proportion (18/31) of NoV-positive children with dehydration required intravenous rehydration. Nucleotide sequence analysis (38/65) of the N-terminal and shell region in the capsid gene revealed that at least six genotypes (GI.4, GII.2, GII.4, GII.7, GII.17, and a potentially novel cluster termed "GII.18-Nica") circulated during the study period, with GII.4 virus being predominant (26/38). The majority (20/26) of those GII.4 strains shared high nucleotide homology (99%) with the globally emerging Hunter strain. The mean viral load was approximately 15-fold higher in children infected with GII.4 virus than in those infected with other G.II viruses, with the highest viral load observed for the group of children infected with GII.4 and requiring intravenous rehydration. This study, the first of its type from a Central American country, suggests that NoV is an important etiological agent of acute diarrhea among children of <2 years of age in Nicaragua.
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| 2. |
- Bucardo, Filemon, et al.
(author)
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Susceptibility of Children to Sapovirus Infections, Nicaragua, 2005–2006
- 2012
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In: Emerging Infectious Diseases. - Atlanta, GA, USA : U.S. Department of Health and Human Services * Centers for Disease Control and Prevention. - 1080-6040 .- 1080-6059. ; 18:11, s. 1875-1878
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Journal article (peer-reviewed)abstract
- We describe the genetic diversity of sapovirus (SaV) in children in Nicaragua and investigate the role of host genetic factors and susceptibility to SaV infections. Our results indicate that neither ABO blood group, Lewis phenotype, nor secretor status affects susceptibility to SaV infection in Nicaragua.
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| 3. |
- Hellysaz, Arash, 1982-, et al.
(author)
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Microbiota do not restrict rotavirus infection of colon
- 2023
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In: Journal of Virology. - : American Society for Microbiology. - 0022-538X .- 1098-5514. ; 97:11
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Journal article (peer-reviewed)abstract
- Rotavirus is associated with extensive infection of the small intestine, whereas colon is considered to be uninfected. Considering that almost all bacteria in the gut colonize the colon, we hypothesized that the microbiota may act as a physical barrier preventing rotavirus infection in the colon in vivo. To address this hypothesis, we used human and mice colonoids, and biopsies of different intestinal segments of untreated and antibiotic-treated adult and infant mice. Rotavirus quantification was performed by qPCR and volumetric 3D imaging of intestinal segments. By 3D imaging, we observed infection in all the small intestinal segments, most extensively in the ileum, with most limited number of infected cells in colon. Broad-spectrum antibiotic treatment yielded no significant change in infection in either ileum or colon of adults and mice pups, although there is a substantial decrease in microbial load. We also show that rotavirus can successfully infect and replicate in colonoids from both mice and humans. Collectively, our data, including novel 3D imaging of the gut, mouse, and human colonoids, conclude that microbiota does not affect rotavirus infection in colon.IMPORTANCEAlterations of the gut microbiome can have significant effects on gastrointestinal homeostasis leading to various diseases and symptoms. Increased understanding of rotavirus infection in relation to the microbiota can provide better understanding on how microbiota can be used for clinical prevention as well as treatment strategies. Our volumetric 3D imaging data show that antibiotic treatment and its consequent reduction of the microbial load does not alter the extent of rotavirus infection of enterocytes in the small intestine and that restriction factors other than bacteria limit the infection of colonocytes.
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| 4. |
- Hopkins, Francis R., et al.
(author)
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Major alterations to monocyte and dendritic cell subsets lasting more than 6 months after hospitalization for COVID-19
- 2023
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In: Frontiers in Immunology. - : Frontiers Media S.A.. - 1664-3224. ; 13
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Journal article (peer-reviewed)abstract
- Introduction: After more than two years the Coronavirus disease-19 (COVID-19) pandemic continues to burden healthcare systems and economies worldwide, and it is evident that the effects on the immune system can persist for months post-infection. The activity of myeloid cells such as monocytes and dendritic cells (DC) is essential for correct mobilization of the innate and adaptive responses to a pathogen. Impaired levels and responses of monocytes and DC to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is likely to be a driving force behind the immune dysregulation that characterizes severe COVID-19.Methods: Here, we followed a cohort of COVID-19 patients hospitalized during the early waves of the pandemic for 6-7 months. The levels and phenotypes of circulating monocyte and DC subsets were assessed to determine both the early and long-term effects of the SARS-CoV-2 infection.Results: We found increased monocyte levels that persisted for 6-7 months, mostly attributed to elevated levels of classical monocytes. Myeloid derived suppressor cells were also elevated over this period. While most DC subsets recovered from an initial decrease, we found elevated levels of cDC2/cDC3 at the 6-7 month timepoint. Analysis of functional markers on monocytes and DC revealed sustained reduction in program death ligand 1 (PD-L1) expression but increased CD86 expression across almost all cell types examined. Finally, C-reactive protein (CRP) correlated positively to the levels of intermediate monocytes and negatively to the recovery of DC subsets.Conclusion: By exploring the myeloid compartments, we show here that alterations in the immune landscape remain more than 6 months after severe COVID-19, which could be indicative of ongoing healing and/or persistence of viral antigens.
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| 5. |
- Månsson, Kristoffer N. T., et al.
(author)
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Improvement in indices of cellular protection after psychological treatment for social anxiety disorder
- 2019
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In: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 9:1
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Journal article (peer-reviewed)abstract
- Telomere attrition is a hallmark of cellular aging and shorter telomeres have been reported in mood and anxiety disorders. Telomere shortening is counteracted by the enzyme telomerase and cellular protection is also provided by the antioxidant enzyme glutathione peroxidase (GPx). Here, telomerase, GPx, and telomeres were investigated in 46 social anxiety disorder (SAD) patients in a within-subject design with repeated measures before and after cognitive behavioral therapy. Treatment outcome was assessed by the Liebowitz Social Anxiety Scale (self-report), administered three times before treatment to control for time and regression artifacts, and posttreatment. Venipunctures were performed twice before treatment, separated by 9 weeks, and once posttreatment. Telomerase activity and telomere length were measured in peripheral blood mononuclear cells and GPx activity in plasma. All patients contributed with complete data. Results showed that social anxiety symptom severity was significantly reduced from pretreatment to posttreatment (Cohen’s d = 1.46). There were no significant alterations in telomeres or cellular protection markers before treatment onset. Telomere length and telomerase activity did not change significantly after treatment, but an increase in telomerase over treatment was associated with reduced social anxiety. Also, lower pretreatment telomerase activity predicted subsequent symptom improvement. GPx activity increased significantly during treatment, and increases were significantly associated with symptom improvement. The relationships between symptom improvement and putative protective enzymes remained significant also after controlling for body mass index, sex, duration of SAD, smoking, concurrent psychotropic medication, and the proportion of lymphocytes to monocytes. Thus, indices of cellular protection may be involved in the therapeutic mechanisms of psychological treatment for anxiety.
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| 6. |
- Nordgren, Johan, 1980-, et al.
(author)
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A FUT2 nonsense mutation (G428A) and Lewis-independent norovirus GI.3 outbreak
- 2009
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Journal article (other academic/artistic)abstract
- Background: Norovirus (NoV) is recognized as the commonest cause of acute gastroenteritis among adults. Previous studies have shown that histo-blood group antigens (HBGAs) and secretor status are associated with susceptibility to symptomatic NoV infection, with non-secretors being almost completely resistant to disease. Here we report on a food-borne GI.3 NoV outbreak affecting 33/83 (40%) individuals. Methods: Secretor status and HBGA expression in saliva were determined with pyrosequencing and ELISA. Virus characterization was performed by sequencing the N/S region and the complete capsid gene. Results: A novel observation was that homozygous carriers of the nonsense FUT2 G428A allele were more susceptible to symptomatic infection than secretors (odds ratio [OR] 1.41 vs 0.71). Consistent with this observation was that Lewis a positive b negative (Lea+b-) individuals showed the highest susceptibility (OR 2.42) compared with other Lewis phenotypes. Blood group B was associated with partial protection (OR 0.27). The capsid gene of the outbreak strain exhibits high amino acid homology with the Kashiwa645 GI.3 strain, previously shown to recognize non-secretor saliva. Conclusion: We describe for the first time a NoV outbreak with Lea+b- individuals homozygous for the G428A nonsense mutation in the FUT2 gene being more susceptible for disease than secretor-positive individuals.
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| 7. |
- Nordgren, Johan, 1980-
(author)
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Norovirus Epidemiology : Prevalence, transmission, and determinants of disease susceptibility
- 2009
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Doctoral thesis (other academic/artistic)abstract
- Norovirus (NoV) is today recognized as the most important agent of acute human gastroenteritis, causing a high number of diarrheal episodes in both adults and children. Outbreaks in hospitals, nursing homes, day-care centers, and from consumption of contaminated food and drinking water are common. Wastewater can be a source of NoV dissemination, e.g. when used for irrigation of crops, or due to shellfish cultivation near the outlet of wastewater treatment plants. Today, at least 25 different genotypes of NoV belonging to two major genogroups (GG) have been observed in humans. These genotypes are associated with different transmission patterns and disease severity in humans. Also host genetic factors, such as presence of ABO antigens and mutations in the FUT2 gene affect susceptibility, and can even render complete resistance to symptomatic infections, but only the most common NoV genotypes have been studied regarding this.In this thesis, we wanted to find prevention strategies for NoV disease through four studies of NoV epidemiology: Development of a sensitive real-time PCR assay for detection and quantification of human NoVs, characterization of NoV in children with diarrhea in Nicaragua, investigation of the prevalence and parameters influencing NoV concentration in a wastewater treatment plant in Gothenburg, Sweden, and studying host susceptibility factors in a foodborne NoV outbreak in Jönköping, Sweden.First we developed a real-time PCR assay which can detect and quantify NoV in various settings, both in stool samples of patients, and in wastewater samples from which virus was first concentrated using ultracentrifugation. This assay was found to be more sensitive than commercial immunological assays and conventional PCR methods. The assay is furthermore able to differentiate between the two major human genogroups of NoV using melting curve analysis, which provides valuable information about the circulating NoV strains.The survey of NoV in pediatric diarrhea in Nicaragua revealed a large impact of NoV, both in community and hospital based settings, with 15% of the severe diarrhea cases attributed to NoV. Peaks of clinically diagnosed NoV gastroenteritis were associated with emerging variants of genotype GGII.4, largely replacing the many different NoV genotypes circulating before the peak of diarrheal cases. Children infected with the GGII.4 genotype were found to shed more virus compared to children infected with other genotypes, which could partly explain the high transmission of GGII.4.At the wastewater treatment plant in Gothenburg, both NoV GGI and GGII were detected during a whole year, not only during the winter season when clinical cases are common. This indicates that NoV infections are frequently occurring at clinical and/or sub-clinical levels in the community. During winter, GGII was present in high concentrations, whereas GGI concentration increased to higher levels than GGII in summer, possibly due to the emergence of new genotypes following the winter outbreaks. The levels of NoV GGI were stable during the year, and hence incoming concentrations were affected by dilution factors such as rain. Primary treatment and treatment in a conventional, non-nitrifying activated sludge system reduced the NoV concentration by a factor of about 30. The detection of NoV in outgoing water, together with the low reduction and lack of correlation to indicator bacteria, suggest that better monitoring tools for virus in wastewater are warranted to reduce environmental contamination.A foodborne NoV outbreak in Jönköping in October 2007, by a NoV GGI.3 strain, revealed a surprising pattern of host susceptibility. In contrast to previous findings, this strain infected individuals irrespective of secretor status and Lewis (Le) phenotype, with non-secretors and Lea+bindividuals having a higher risk of disease. Individuals with blood group B had a partial protection to symptomatic infection, but none of the host factors investigated mediated complete resistance. Furthermore, we observed differences in susceptibility regarding homozygosity and heterozygosity in the FUT2 gene, with heterozygous secretor-positive individuals being more susceptible to symptomatic NoV infection than homozygous secretors.In summary, the developed LUX real-time PCR assay was successfully used in all studies in this thesis, which yielded important information about the prevalence and transmission of NoV. We observed the emergence of GGII.4 variants, causing the majority of diarrheal cases in children, largely replacing the other circulating genotypes, possibly due to better replication leading to a higher viral shedding. After the peak of NoV-induced diarrheal episodes, the incidence of GGII.4 decrease and other strains emerge which can infect people not previously exposed. This was observed in the foodborne outbreak in Jönköping, where individuals expected to be resistant to NoV were infected, and indeed had a higher risk of developing disease. A similar seasonal pattern was also indirectly observed in wastewater, with high levels of GGII in winter, which subsequently declined, followed by an increase of GGI in summer. Taken together, these results provide a better insight into the epidemiology of the virus, which hopefully can lead to better preventive measures for NoV gastroenteritis.
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| 8. |
- Nordgren, Johan, 1980-, et al.
(author)
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Novel light-upon-extension real-time PCR assays for detection and quantification of genogroup I and II noroviruses in clinical specimens
- 2008
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In: Journal of Clinical Microbiology. - 0095-1137 .- 1098-660X. ; 46:1, s. 164-170
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Journal article (peer-reviewed)abstract
- Norovirus is now recognized as the leading cause of nonbacterial acute gastroenteritis in adults, causing numerous outbreaks worldwide. We have developed two novel light-upon-extension (LUX) real-time PCR assays for detection and quantification of norovirus genogroups I and II. The LUX system uses a fluorophore attached to one primer having a self-quenching hairpin structure, making it cost-effective and specific. The assays were evaluated against clinical stool specimens (n = 103) from Sweden and Nicaragua and compared to established methods. The norovirus assay detected more positive stool specimens (47/103) than conventional PCR (39/103) and corresponded to a TaqMan real-time PCR, with the exception of one specimen. Furthermore, the assays correctly identified all (n = 11) coded control specimens in a reference panel containing various genogroups and genotypes. Both LUX real-time PCR assays had a wide dynamic range, detecting from < or = 10(1) to 10(7) genes per reaction, resulting in a theoretical lower limit of < or = approximately 20,000 viruses per gram of stool. No cross-reactivity was noticed with specimens containing other enteric viruses, and by using melting curve analysis we could differentiate between norovirus genogroups I and II.
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| 9. |
- Nordgren, Johan, 1980-, et al.
(author)
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Reovirus
- 2021. - 2
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In: Medicinsk mikrobiologi & immunologi. - Lund : Studentlitteratur AB. - 9789144123578 ; , s. 468-473
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Book chapter (other academic/artistic)abstract
- I familjen Reoviridae finns det femton genera (släkten), varav fyra innehåller arter som infekterar människor. Namnet Reoviridae kommer från "respirotory enteric orphan virus". Med termen "orphan virus" menas virus som inte är associerat med någon känd sjukdom. Ortoreovirus som infekterar däggdjur identiferades på 1950-talet, och finns i tre serotyper. Det är fortfarande osäkert om dessa virus ger sjukdom hos människa, men antikroppsstudier visar att infektionen är vanlig. Ortoreovirus har på senare år uppmärksammats vid cancerbehandling, då de framför allt förökar sig i celler som aktiveras av onkogenen Ras. De infekterade cellerna lyseras och virusets unika onkolytiska egenskaper utvärderas för närvarande i ett flertal behandlingsstudier mot olika cancerformer. Rotavirus identifierades år 1973, och är den dominerande humanpatogenen bland Reoviridae. Rotavirus klassificeras i tio arter, A-J, och av dessa kan grupp A, B, C och H infektera människan. Rotavirus grupp A orsakar mer än 90 procent av alla rotavirusinfektioner världen över och står i Sverige för majoriteten av alla akuta barndiarréer. Studier har visat att mer än 50 procent av de mag-tarminfektioner (gastroenteriter) hos barn upp till 15 år som kräver sjukhusvård orsakades av rotavirus. I låginkomstländer är rotavirusinfektioner hos småbarn en stor dödsorsak. Den kliniska betydelsen av grupp A-rotavirus har gjort att immunologisk och biokemisk kunskap om rotavirus i huvudsak kommer från grupp A-stammar. Rotavirus är den enda kliniskt viktiga humanpatogenen inom Reoviridae och resten av kapitlet kommer att handla om rotavirus.
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| 10. |
- Reyes, Yaoska
(author)
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Norovirus and rotavirus susceptibility : studies from a Nicaraguan birth cohort
- 2022
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Doctoral thesis (other academic/artistic)abstract
- Norovirus and rotavirus are major causes of pediatric acute gastroenteritis (AGE). It is estimated that norovirus is responsible for ~20% of all diarrheal diseases in children worldwide and causes approximately 200,000 deaths each year, mostly in young children and the elderly. Despite this vast disease burden, there is no licensed vaccine available. The introduction of universal infant rotavirus vaccination has led to marked reductions in diarrhea incidence and diarrhea-associated mortality in children. However, rotavirus continues to cause a high disease burden, particularly in low- and middle-income countries (LMIC), associated with an estimated 128,500 deaths in young children. Susceptibility to both norovirus and rotavirus AGE is strongly associated with the secretor phenotype (expression of specific glycans in mucosa and secretions). This, along with the Lewis phenotype and ABO group form the differential expression of histo-blood group antigens (HBGAs) in the mucosa. These HBGAs can act as putative receptors or attachment factors facilitating infection of these viruses. The overall aim of this thesis was to address outstanding questions regarding susceptibility and immunity to norovirus and rotavirus infections in children. These questions are of relevance for understanding the effects of a future norovirus vaccine and factors influencing vaccine protection. Our questions were addressed by investigating norovirus and rotavirus disease burden, molecular epidemiology, and the role of HBGAs in susceptibility in children enrolled in a rotavirus-vaccinated birth cohort in Nicaragua. We further estimated the breadth and duration of immune response and protection after the first norovirus AGE episode. Our results showed that the incidence of rotavirus and norovirus was 9.3 and 21.9 per 100 child-years, respectively. Several different norovirus genotypes were observed (n=13), the most common being GII.4 (42%), GI.3 (18%), GII.12 (9%) and GII.17 (9%). Genotype GII.4 was not only the most common genotype but also infected children earlier in life and caused more severe AGE episodes compared to other genotypes. In contrast, the distribution of rotavirus genotypes was limited and dominated by animal-derived strains and the absence of the wild-type G1P[8] genotype, which is the component of the Rotarix vaccine used in Nicaragua. Secretor children had the highest risk of norovirus AGE, with the predominant and clinically more severe GII.4 genotype only observed in secretors. Secretor children also had the highest risk for rotavirus AGE after vaccination. This is of particular interest since previous studies have observed that non-secretors have a less immune response after vaccination of the live oral rotavirus vaccines. Hence, the mediation of protection against rotavirus AGE for these children is likely due to genetic resistance to wild-type infections and not by vaccine-induced immune protection. Using surrogate neutralization assays, we observed that the antibody-mediated immune response after the first AGE episode of norovirus GII.4 persisted for about 19 months, thus suggesting a relatively long-term protection. We further found that the immune response against GII.4 was genotype-specific in a significant proportion (60%) of children. The multitypic response exhibited in some children could be due to asymptomatic infections with two or more genotypes over the studied period. Using statistical models, we found that one episode of norovirus GI and norovirus GII conferred approximately 33% and 80% reduced hazard against future genogroup-specific episodes in the first 3 years of life, respectively. In summary, the results presented in this thesis suggest that a pediatric norovirus vaccine including norovirus GII.4, and given early in life, would significantly reduce the high burden of diarrheal disease in young children, particularly for secretors.
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