Deficient IFN Signaling by Myeloid Cells Leads to MAVS-Dependent Virus-Induced Sepsis
Figure 9
Model of sepsis after viral infection of CD11c+ DC or LysM+ myeloid cells.
Myeloid cells that lack signaling (due to Ifnar gene deletion, pharmacological blockade with anti-IFNAR MAbs, or IFN signaling antagonism by viruses) are more susceptible to infection. In the context of WNV infection, increased viral replication results in enhanced RNA PAMP generation, which activates MAVS via recruitment to the mitochondria. This results in downstream activation of IRF-3 and NF-κB and also assembly of the NLRP3 inflammasome. IRF-3 activation and nuclear translocation promotes induction of a limited set of ISGs. NF-κB activation and nuclear translocation promotes expression of pro-inflammatory cytokines (e.g., IL-6 and TNF-α) and chemokines (CCL5 and CXCL10). Soluble TNF-α can modulate endothelial cells function and integrity and also induce complement factor expression in myeloid and hepatic cells, including C3 and factor B. Higher levels of C3 and factor B in the context of increased WNV in plasma results in excessive complement activation (via the alternative pathway), which can liberate the C3a and C5a anaphylatoxins. Along with TNF-α, these promote changes to vascular permeability and tone that result in hypotension and visceral organ (e.g., liver and kidney) damage. Independently, excessive virus infection in restricted tissues (e.g., spleen and LN) can cause organ damage. The pathological effects of this cascade can be mitigated by administration of blocking MAbs to TNF-α or C5.