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Norovirus is the most common cause of acute non-bacterial gastroenteritis. Immunocompromised patients can become chronically infected, with or without symptoms. In Europe, common variable immunodeficiency (CVID) is one of the most common inborn errors of immunity. A potentially severe complication is CVID-associated enteropathy, a disorder with similar histopathology to celiac disease. Studies suggest that chronic norovirus infection may be a contributor to CVID enteropathy, and that the antiviral drug ribavirin can be effective against norovirus. Here, a patient with CVID-like disease with combined B- and T-cell deficiency, had chronic norovirus infection and enteropathy. The patient was routinely administered subcutaneous and intravenous immunoglobulin replacement therapy (SCIg and IVIg). The patient was also administered ribavirin for -7.5 months to clear the infection. Stool samples (collected 2013-2016) and archived paraffin embedded duodenal biopsies were screened for norovirus by qPCR, confirming a chronic infection. Norovirus genotyping was done in 25 stool samples. For evolutionary analysis, the capsid (VP1) and polymerase (RdRp) genes were sequenced in 10 and 12 stool samples, respectively, collected before, during, and after ribavirin treatment. Secretor phenotyping was done in saliva, and serum was analyzed for histoblood group antigen (HBGA) blocking titers. The chronic norovirus strain formed a unique variant subcluster, with GII.4 Den Haag [P4] variant, circulating around 2009, as the most recent common ancestor. This corresponded to the documented debut of symptoms. The patient was a secretor and had HBGA blocking titers associated with protection in immunocompetent individuals. Several unique amino acid substitutions were detected in immunodominant epitopes of VP1. However, HBGA binding sites were conserved. Ribavirin failed in treating the infection and no clear association between ribavirin-levels and quantity of norovirus shedding was observed. I, Funding Agencies|Region Ostergotland [ALF-LIU-934451]; Karolinska Institute [ALF-KI-K23003073]; Swedish Research Council [2018-02862]

The emergence of pandemic GII.4 norovirus (NoV) strains has been proposed to occur due to changes in receptor usage and thereby to lead to immune evasion. To address this hypothesis, we measured the ability of human sera collected between 1979 and 2010 to block glycan binding of four pandemic GII. 4 noroviruses isolated in the last 4 decades. In total, 268 sera were investigated for 50% blocking titer (BT50) values of virus-like particles (VLPs) against pig gastric mucin (PGM) using 4 VLPs that represent different GII. 4 norovirus variants identified between 1987 and 2012. Pre- and postpandemic sera (sera collected before and after isolation of the reference NoV strain) efficiently prevented binding of VLP strains MD145 (1987), Grimsby (1995), and Houston (2002), but not the Sydney (2012) strain, to PGM. No statistically significant difference in virus-blocking titers was observed between pre- and postpandemic sera. Moreover, paired sera showed that blocking titers of amp;gt;= 160 were maintained over a 6-year period against MD145, Grimsby, and Houston VLPs. Significantly higher serum blocking titers (geometric mean titer [GMT], 1,704) were found among IgA-deficient individuals than among healthy blood donors (GMT, 90.9) (P amp;lt; 0.0001). The observation that prepandemic sera possess robust blocking capacity for viruses identified decades later suggests a common attachment factor, at least until 2002. Our results indicate that serum IgG possesses antibody-blocking capacity and that blocking titers can be maintained for at least 6 years against 3 decades of pandemic GII. 4 NoV. IMPORTANCE Human noroviruses (NoVs) are the major cause of acute gastroenteritis worldwide. Histo-blood group antigens (HBGAs) in saliva and gut recognize NoV and are the proposed ligands that facilitate infection. Polymorphisms in HBGA genes, and in particular a nonsense mutation in FUT2 (G428A), result in resistance to global dominating GII. 4 NoV. The emergence of new pandemic GII. 4 stra, Funding Agencies|Swedish Research Council [320301, 8266]; Swedish Foundation for Strategic Research

Background: Tick-borne encephalitis virus (TBEV) infections can be asymptomatic or cause moderate to severe injuries of the nervous system. We previously reported that a nonfunctional chemokine receptor 5 (CCR5) and a functional Toll-like receptor 3 (TLR3) predispose adults to clinical tick-borne encephalitis (TBE). This study expands our previous findings and further examines polymorphisms in CCR5 and TLR3 genes in different age and disease severity groups. Methods: 117 children and 129 adults, stratified into mild, moderate and severe forms of TBE, and 103 adults with severe TBE were analyzed. 135 healthy individuals and 79 patients with aseptic meningoencephalitis served as controls. CCR5 delta 32 and rs3775291 TLR3 genotypes were established by pyrosequencing, and their frequencies were analyzed using recessive genetic, genotype and allelic models. Findings: The prevalence of CCR5 Delta 32 homozygotes was higher in children (2.5%), in adults with severe TBE (1.9%), and in the combined cohort of TBE patients (2.3%) than in controls (0%) (pless than0.05). The nonfunctional homozygous TLR3 genotype was less prevalent among the combined TBE cohort (11.5%) than among controls (19.9%) (p = 0.025), but did not differ between children TBE and controls. The genotype and allele prevalence of CCR5 and TLR3 did not differ in children nor adult TBE cohorts stratified by disease severity. However, in the severe adult TBE cohort, homozygous functional TLR3 genotype and wt allele were less prevalent compared to the adult cohort with the whole disease severity spectrum (44.4% vs 59.8% p = 0.022 and 65.2% vs 76.4% p = 0.009; respectively). Conclusions: Independently of age, nonfunctional CCR5D32 mutation is a significant risk factor for development of clinical TBE, but not for disease severity. The polymorphism of TLR3 gene predisposes to clinical TBE in adults only and may be associated with disease severity. Further studies are needed to clarify the role of these polymorphisms, Funding Agencies|Research Council of Lithuania [MIP-11174]; Swedish Research Council [3485]

In November 2004, 116 individuals in an elderly nursing home in El Grao de Castellón, Spain were symptomatically infected with genogroup II.4 (GII.4) norovirus. The global attack rate was 54.2%. Genotyping of 34 symptomatic individuals regarding the FUT2 gene revealed that one patient was, surprisingly, a non-secretor, hence indicating secretor-independent infection. Lewis genotyping revealed that Lewis-positive and negative individuals were susceptible to symptomatic norovirus infection indicating that Lewis status did not predict susceptibility. Saliva based ELISA assays were used to determine binding of the outbreak virus to saliva samples. Saliva from a secretor-negative individual bound the authentic outbreak GII.4 Valencia/2004/Es virus, but did not in contrast to secretor-positive saliva bind VLP of other strains including the GII.4 Dijon strain. Amino acid comparison of antigenic A and B sites located on the external loops of the P2 domain revealed distinct differences between the Valencia/2004/Es and Dijon strains. All three aa in each antigenic site as well as 10/11 recently identified evolutionary hot spots, were unique in the Valencia/2004/Es strain compared to the Dijon strain. To the best of our knowledge, this is the first example of symptomatic GII.4 norovirus infection of a Le(a+b-) individual homozygous for the G428A nonsense mutation in FUT2. Taken together, our study provides new insights into the host genetic susceptibility to norovirus infections and evolution of the globally dominating GII.4 viruses., Original Publication: Beatrice Carlsson, Elin Kindberg, Javier Buesa, Gustaf E Rydell, Marta Fos Lidón, Rebeca Montava, Reem Abu Mallouh, Ammi Grahn, Jesús Rodríguez-Díaz, Juan Bellido, Alberto Arnedo, Göran Larson and Lennart Svensson, The G428A nonsense mutation in FUT2 provides strong but not absolute protection against symptomatic GII.4 Norovirus infection., 2009, PLoS ONE, (4), 5, e5593. http://dx.doi.org/10.1371/journal.pone.0005593 Licensed under Creative Commons

In this novel study, we have for the first time identified evolutionarily conserved capsid residues in an individual chronically infected with norovirus (GGII.3). From 2000 to 2003, a total of 147 P1-1 and P2 capsid sequences were sequenced and investigated for evolutionarily conserved and functionally important residues by the evolutionary trace (ET) algorithm. The ET algorithm revealed more absolutely conserved residues (ACR) in the P1-1 domain (47/53, 88 %) as compared with the P2 domain (86/133, 64 %). The capsid P1-1 and P2 domains evolved in time-dependent manner, with a distinct break point observed between autumn/winter of year 2000 (isolates P1, P3 and P5) and spring to autumn of year 2001 (isolates P11, P13 and P15), which presumably coincided with a change of clinical symptoms. Furthermore, the ET analysis revealed a similar receptor-binding pattern as reported for Norwalk and VA387 strains, with the CS-4 and CS-5 patch (Norwalk strain) including residues 329 and 377 and residues 306 and 310, respectively, all being ACR in all partitions. Most interesting was that residues 343, 344, 345, 374, 390 and 391 of the proposed receptor A and B trisaccharide binding site (VA387 strain) within the P2 domain remained ACR in all partitions, presumably because there was no selective advantage to alter the histo blood group antigens (HBGA) receptor binding specificity. In conclusion, this study provides novel insights to the evolutionary process of norovirus during chronic infection.

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.

Background. Sapovirus (SaV) infections are increasing globally but there is no information available regarding factors determining susceptibility to SaV infections in the Caucasian population. Methods. Saliva samples were collected from 64 individuals with sapovirus gastroenteritis in Denmark between October 2008 and November 2010. These were genotyped for the FUT2 G428A nonsense mutation (secretor status) and phenotyped for ABO and Lewis histo-blood groups. Results. We found that neither secretor status nor Lewis phenotype, were associated with susceptibility to symptomatic infection with SaV. However, individuals of histo-blood groups B and AB had significantly lower risk to be infected (OR 0.18, p≤0.01 and OR 0.10, p<0.05, respectively). For 39 of the 64 SaV positive samples viral strains were genotyped and 41%, (16/39) belonged to genotype GI.2, 10% was GI.1 (4/39), 2.5% was GI.5 (1/39), 8% was GII.1 (3/39), 5% was GII.4 (2/39), 18% was GIV (7/39) and 15.5% was GV (6/39). Conclusion. This is the first report investigating the role of host genetic factors in SaV susceptibility in the Caucasian population. We found a reduced risk of infection in individuals with blood group B (and AB), but no association to the FUT2 G428A nonsense mutation determining secretor status nor to the Lewis status.