Tickborne encephalitis (TBE) virus infections can be asymptomatic or cause moderate to severe injuries of the central nervous system. Why some individuals develop severe disease is unknown, but a role for host genetic factors has been suggested. To investigate whether chemokine receptor CCR5 is associated with TBE, CCR5Delta32 genotyping was performed among Lithuanian patients with TBE (n=129) or with aseptic meningoencephalitis (n=76) as well as among control subjects (n=134). We found individuals homozygous for CCR5Delta32 (P= .026) only among patients with TBE and a higher allele prevalence among patients with TBE compared with the other groups studied. CCR5Delta32 allele prevalence also increased with the clinical severity of disease.

Noroviruses have emerged as a major cause of acute gastroenteritis in humans of all ages. Despite high infectivity of the virus and lack of long-term immunity, volunteer and authentic studies has suggested the existence of inherited protective factors. Recent studies have shown that histo-blood group antigens (HBGAs) and in particular secretor status controlled by the alpha1,2fucosyltransferase FUT2 gene determine susceptibility to norovirus infections, with nonsecretors (FUT2-/-), representing 20% of Europeans, being highly resistant to symptomatic infections with major strains of norovirus. Moreover, the capsid protein from distinct strains shows different HBGA specificities, suggesting a host-pathogen co-evolution driven by carbohydrate-protein interactions.

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 Lea+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.

Nonsecretors were highly susceptible to norovirus GI.3 in a foodborne outbreak.

A total of 61 individuals involved in five norovirus outbreaks in Denmark were genotyped at nucleotides 428 and 571 of the FUT2 gene, determining secretor status, i.e., the presence of ABH antigens in secretions and on mucosa. A strong correlation (P ‫؍‬ 0.003) was found between the secretor phenotype and symptomatic disease, extending previous knowledge and confirming that nonsense mutations in the FUT2 gene provide protection against symptomatic norovirus (GGII.4) infections.Volunteer studies have shown that a subset of individuals are not affected by vomiting and diarrhea after challenges with noroviruses (1,16,19), and this information, together with the fact that attack rates seldom exceed 70% (4), suggests that inherited factors act to prevent certain individuals from symptomatic norovirus disease. Indeed, experimental and volunteer studies have indicated a correlation between secretor status and susceptibility to Norwalk virus (genogroup I norovirus) infections (3,12,14). These observations were recently confirmed and extended to also include authentic outbreaks by genogroup II viruses (17), which is the clinically most common genogroup of norovirus (9). Current knowledge thus suggests that secretor status determined by polymorphisms in the FUT2 gene is strongly associated with resistance to norovirus infections (3,11,12,17). Further support for this hypothesis is also the fact that nonsecretor and Lewis a-positive individuals have significantly lower antibody prevalence and titer to norovirus GGII than secretor and Lewis b-positive individuals (10). The association between secretor status and norovirus susceptibility is not fully understood, but transfection of the FUT2 gene to nonpermissive cells has been shown to increase cell susceptibility to norovirus infection (14), suggesting that the H antigen or a related structure acts as a receptor for the virus.FUT2 encodes an ␣(1,2)fucosyltransferase, which adds a fucose molecule to the H-type 1 precursor, giving the H-type 1 antigen. H-type 1 can, in contrast to its precursor, work as a precursor for the A and B blood group antigens. FUT2 determines the secretor status, which is the presence or absence of blood group ABH antigens on mucosal surfaces and in secretions such as saliva (5). Individuals carrying the secretor genotypes (SeSe or Sese) secrete the H antigen with or without A and/or B antigens, while individuals of the nonsecretor genotype (sese) do not. The polymorphisms found in the FUT2 gene show high ethnic specificity (8, 13), with a nonsense mutation at nucleotide 428 associated with the Caucasian populations (5, 8) The majority of the positive samples (90%) were submitted from hospitals, representing at least 30 different hospitals and situated in all parts of Denmark. For detection of norovirus in stool samples, purified viral RNA was reverse transcribed and PCR amplified (RT-PCR kit; QIAGEN, Hilden, Germany) by using the primers JV12 and JV13 essentially as described earlier (17,18). The PCR products (285 bp after trimming of the primer se...

Host genetic resistance to Norovirus (NoV) has been observed in challenge and outbreak studies in populations from Europe, Asia, and USA. In this study, we have investigated if histo-blood group antigens can predict susceptibility to diarrhea caused by NoV in Nicaragua, Central America, and if this can be reflected in antibody-prevalence and titer to NoV among individuals with different histo-blood group antigen phenotypes. Investigation of 28 individuals infected with NoV and 131 population controls revealed 6% of non-secretors in the population and nil non-secretors among patients infected with NoV, suggesting that non-secretors may be protected against NoV disease in Nicaragua. Surprisingly, 25% of the population was Lewis negative (Le(a-b-)). NoV infections with genogroup I (GI) and GII occurred irrespective of Lewis genotype, but none of the Lewis a positive (Le(a + b-)) were infected. The globally dominating GII.4 virus infected individuals of all blood groups except AB (n = 5), while the GI viruses (n = 4) infected only blood type O individuals. Furthermore, O blood types were susceptible to infections with GI.4, GII.4, GII.7, GII.17, and GII.18-Nica viruses, suggesting that secretors with blood type O are susceptible (OR = 1.52) and non-secretors resistant. The overall antibody-prevalence to NoV GII.3 VLP was 62% with the highest prevalence among blood type B carriers (70%) followed by A (68%) and O (62%). All four investigated individuals carrying blood type AB were antibody-negative. Among secretors, 63% were antibody-positive compared to 33% among non-secretors (P = 0.151). This study extends previous knowledge about the histo-blood group antigens role in NoV disease in a population with different genetic background than North American and European.

A functional TLR3 is a risk factor for TBEV infection.

Norovirus, the cause of winter vomiting disease, has emerged in recent years to be a major cause of sporadic and epidemic gastroenteritis worldwide. The virus has been estimated to cause >200,000 deaths each year in developing countries. Although the virus is highly contagious, volunteer and field studies have shown that a subset of individuals appears resistant to infections. A single nucleotide mutation (G428A) in the fucosyltransferase gene (FUT2) on chromosome 19 provides strong protection from infection in 20% of the white population. Histo-blood group ABO(H) antigens with terminal fucose are believed to function as receptors for human norovirus in the gastrointestinal tract, but also negatively charged potential receptors have been identified. Norovirus infection is a unique example where a single nucleotide mutation in a fucosyltransferase gene plays a crucial role in susceptibility to one of the most common viral diseases. This review discusses the role of host genetics and carbohydrate structures in susceptibility to winter vomiting disease.