Cytokine signaling of IL-1β, IL-23, IL-17A, CCL7, CXCL10, TRAIL, CD40L, and BAFF provides protection against acute WNV infection in mice; IL-10 and IL-22 aid in WNV pathogenicity; IL-6 and IL-12 had no apparent effect during infection; and CCL2, TNF-α, and FasL roles remain elusive. Here, CD40LG is linked to infection.