Recent studies have shown that host genetic factors such as the
FUT2 and
FUT3 genotypes strongly affect human susceptibility to NoVs [
20]. Due to the lack of a good animal or in vitro model to investigate NoV pathogenesis, evidences in this field have been obtained both from volunteers studies and from outbreaks of natural infections [
5], like the outbreak here reported.
In this outbreak occurred in Valencia in 2012, although few individuals were affected, different susceptibility to NoV diarrhoea in secretor-positive and secretor-negative individuals was observed, reinforcing the idea that non-secretors are naturally protected to NoV infections [
21]. Surprisingly, one of the stool samples positive for NoV by RT-PCR was from a secretor-negative individual. This result is highly relevant since it indicates that NoV replication occurred in the non-secretor individual but without causing symptoms. This observation was confirmed with the finding of a high anti-NoV IgA titer in the saliva of this non-secretor individual, similar to the titers in secretor-positive patients, thus showing that infection had indeed occurred. In the past we also described a non-secretor that was susceptible to NoV GII.4-Hunter_2004 NoV infection, but in that case symptoms were also present [
14]. In order to become symptomatically infected (2004 outbreak) or asymptomatically (2012 outbreak) non-secretors must display receptors for NoVs, raising the question of what other receptors, not yet known, may be implicated in NoV infections. A recent study showed that NoV VLPs did not colocalize with H or Lewis antigens in epithelial cells, reinforcing the idea that other receptors are involved in NoV infections [
22]. Gangliosids have also shown to bind NoVs [
23]. In addition, enteric bacteria also seem to play a role in NoV infections acting themselves as co-receptors [
12,
24,
25]. Another interesting result is that the secretor-negative individual did not develop IgG antibodies against NoV, in contrast to what it was observed with the salivary IgA. It can be argued that the absence of symptoms could be due to a lower infectivity of the virus in the secretor-negative individual, in whom it only elicited a mucosal immune response. On the other hand, high IgG titers were found in serum samples from infected secretors at the outbreak. Seroconversion occurred 2 weeks after the infection and the IgG titers did not decrease 1 year after infection. These results are relevant, since it has been reported that previous infections do not protect against subsequent NoV infections [
26]. Our results suggest that this lack of protection might be due to viral evolution [
3,
27‐
29] instead of a low immune stimulation. In fact, several seroepidemiologic studies of NoV-specific antibodies in different populations have been performed [
19,
30,
31], showing high seroprevalence levels and consequently a good immunogenicity of NoVs. The blocking assays showed that serum IgG antibodies were able to block the attachment of VLPs to saliva, reinforcing the idea that NoV infections elicit protective immunity.