Comparison of severe H5N1 infections with uncomplicated seasonal influenza infections revealed a pattern of increased viral load and elevated cytokine production in the respiratory tract and serum [75, 83] . The robust cytokine/chemokine response often seen in H5N1 infected patients (hypercytokinemia) is believed to be at least partially responsible for the observed pathogenesis and high fatality of H5N1 infection. Elevated cytokines both in vivo and in vitro include IFNγ, sIL-2R, IL-6, IP-10, TNFα, and MCP-1 [75, [84] [85] [86] . Mouse models of H5N1 infection also demonstrate elevated levels of MCP-1, MIP-1α, IL-6, and IFNγ, even compared to 1918 H1N1 virus infection [87] . Knocking out IL-1R in mice exacerbates H5N1 pathology and suggests that IL-1β-mediated signalling may be important in protection [75] . In ferret models, IP-10 upregulation and signaling through CXCR3 was determined to be a major component of H5N1 disease severity and mortality [88] . Expression of many of these chemokines and cytokines in humans is modulated by SNPs in their promoter regions, including MCP-1 −2518 G/A [89] , IP-10 −201G/A [90] , and IL-6 −174G/C [91] . Genetic variants affecting expression and function of chemokine receptors may also modulate influenza pathogenesis, as CCR5 knock-out mice exhibit increased influenza mortality, whereas CCR2 knockout strains show increased survival ( Table 2) ; both of these effects appear to be related to the kinetics and strength of macrophage recruitment to the lung [42] . In vitro evidence further suggests upregulation of CCR5 on monocyte-derived macrophages that may enhance pathogenesis [92] .