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Highly Neurovirulent Viruses Invade and Spread in the Brain Using the Host Reactions Triggered by Infection

Rihito Watanabe and Masatoshi Kakizaki

Coronaviruses (CoVs) have relatively high mutation and RNA recombination rates and undergo rapid crossspecies transmission events in vitro and in vivo. The viruses have evolved diverse strategies to evade, blocking host immune responses, and resulting in an emergence of highly virulent CoVs to cause fatal diseases in human, such as severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). Among CoVs used for experimental studies, the cl-2 virus (cl-2), isolated from a neuropathogenic JHM viral strain (JHMV) of mouse hepatitis virus (MHV), shows extremely high virulence. All mice infected with cl-2 die within 3 days post-inoculation (dpi). Less virulent but still highly neurovirulent mutant viruses, soluble receptor resistant mutant virus (srr7) and Mu-3 virus (Mu-3), have been isolated from cl-2 and srr7, respectively. Although these viruses cause different pictures of neuropathologies with different distribution of viral antigens after infection, they use the same pathway to enter the brain before inducing lesions in the brain parenchyma. The pathway is formed as an astrocytic reticular network (ARN) after infection. The ARN functions as a conduit system in a similar way to a fibroblastic reticular network (FRN) in lymphoid organs. In addition, the viruses induce an immunosuppressive state in infected mice, mimicking endotoxin tolerance (ET), or lipopolysaccharide (LPS) tolerance. The immunosuppressive states are detected by; 1) pathological findings as 1a); a very low -level inflammatory response, 1b); the shrunken spleen, 1c); the refractory state to LPS challenge, and 1d); the local production of anti-inflammatory cytokines by neurons, and by 2) immunological studies, which showed 2a); the systemic production of anti-inflammatory cytokines by eliciting CD11b+Gra-1+ suppressor monocytes/macrophages (Mo/Mas).In addition, cultured splenic cells and Mo/Mas after infection exhibit 2b); low-level responses to stimulation of toll-like receptors (TLRs) 4 and 7, and 2c); the induction of Lewis X carbohydrate structure (Lex), which can trigger the C-type lectin-like receptor that initiates an immunosuppressive pathway, respectively.