Figure 2.

(A) Simplified schematic of the initial pathogenesis of WNV infections after inoculation of the virus into the skin. After intradermal inoculation by infected mosquitoes, WNV replicates in skin cells, specifically in Langherhans cells (LCs). Infected LCs migrate to regional lymph nodes and pass through efferent lymphatic vessels to reach the bloodstream. This primary viremia results in the infection of leukocytes and of peripheral tissues such as the spleen, liver and kidneys; (B) Simplified schematic of the regulation of BBB permeability following WNV infection and entry into the brain. WNV infects and replicates in leukocytes, which act as reservoirs for the virus in a Trojan Horse-like fashion. Viral sensors (such as TLR3) recognize WNV and initiate the production of matrix metalloproteinases, such as MMP9, and pro-inflammatory cytokines, such as TNFα, which have both been shown to increase BBB permeability and facilitate WNV dissemination into the brain. Infected microglia respond by releasing pro-inflammatory mediators (TNFα, iNOS, Cox2, IL6, and IL1β), which cause neuronal death. Infected astrocytes also produce inflammatory mediators that can amplify the local immune response and modify BBB permeability. Neuronal death results, in large part, from an upregulation of the apoptotic caspase-3 and caspase-9 pathways following infection with North American isolates. BBB: blood-brain barrier, TLR3: Toll-like Receptor 3, MMP9: matrix metalloproteinase 9, TNFα: tumor necrosis factor alpha, iNOS: nitric oxide synthase, Co-2: cyclooxygenase 2, IL6: interleukin 6, IL1β: interleukin 1 beta.