Fig. 11

Proposed model for IFN-I role in inducing CNS neuroinflammation through the peripheral restriction of JEV dissemination. In IFN-I signal-competent hosts, JEV first infects locally infiltrated CD11b⁺Ly-6C⁺ monocytes and their matured CD11b⁺Ly-6C⁺F4/80⁺ macrophages in primary inoculation tissues (footpad) and then in local LNs (popliteal LNs). Virus produced in these sites gains entry into the bloodstream via CD11b⁺Ly-6C⁺ monocytes, causing primary viremia. Subsequently, the virus is carried to larger organs such as the liver, kidney, intestine, and so forth, but tissue-resident cells in those organs are not permissive to virus replication. Later (5–7 dpi), CD11b⁺Ly-6C⁺ monocytes infected with JEV gain access to the CNS, which inoculate virus to very permissive neuron cells, thereby resulting in encephalitis. In contrast, JEV is provided with higher levels in IFN-I signal-incompetent mice after infecting infiltrated CD11b⁺Ly-6C⁺ monocytes and their matured CD11b⁺Ly-6C⁺F4/80⁺ macrophages in primary inoculation sites and then in local LNs. Virus appears in the bloodstream through circulating CD11b⁺Ly-6C⁺ monocytes, and subsequently infects permissive tissue-resident cells (hepatocytes, enterocytes, etc.) in the liver, kidney, and intestine, and so forth. Infection of various tissue-resident cells in larger organs with JEV brings about a fatal “cytokine storm” in IFN-I signal-incompetent hosts within 2 dpi, thereby inducing multiple organ failure rather than encephalitis