Severity. The precise impact of host genetic variability on H5N1 susceptibility remains somewhat controversial, given the limited case data available and the relatively low number of published studies. A case study in Indonesia [52] found evidence of clusters of H5N1 infection among blood relatives that may be indicative of shared genetic susceptibility, but the authors were unable to rule out a shared viral exposure or altered viral pathogenesis in any of the clusters. Similar observations in a number of additional studies have prompted several authors to suggest a potentially strong genetic basis for H5N1 susceptibility [53] [54] [55] [56] [57] . A compilation of confirmed H5N1 cases worldwide found that, on average, 22% of cases occurred in clusters, and only 6% of cases within the clusters were not genetically related to other cluster members [1] . While this data does not conclusively point to genetic variation as an important determinant of susceptibility, it is important to note that human-to-human transmission of H5N1 is very rare, and therefore does not likely explain the high degree of genetic relatedness among cases [1] . It would also be expected that clusters of nonrelated individuals working in the poultry industry would be more prominent than genetically related clusters, if people are at equal risk of infection [1] . Some studies, however, have suggested that the observed clustering of infections among families could occur due to chance alone at the low rates of infection that are observed in H5N1 and highlight the difficulty in drawing conclusions from the currently available data [58] . TLR3 908T/C Missense mutation identified in a patient with influenza-associated encephalopathy [45] host/virus interactions and the qualities of a protective immune response. To date, a number of candidate genes have been identified from both human and mouse immunobiology studies. Mouse models of influenza infection have the advantage of being able to dissect gene expression kinetics and the characteristics of the immune response at various stages of infection. Comparison of infection across inbred mouse lines demonstrates significant differences in viral titre and core temperature, as well as distinct patterns of immune gene upregulation, suggesting an important contribution of host genetic background [59] .