MyD88 signaling in myeloid cells induces gastrointestinal tract injury and systemic inflammation after West Nile virus infection.

Humans with autoantibodies to type I interferons (IFNs) are at higher risk for neurological disease after West Nile virus (WNV) infection. IFN signaling deficient WNV-infected mice develop greater inflammation in the brain, which correlates with loss of gut barrier integrity. Here, we investigate the immune pathways that mediate this virus-gut-brain axis of inflammation. Myd88(-/-) mice administered anti-IFNAR1 antibody and infected with WNV exhibit reduced GI tract damage and inflammation. GI tract injury caused by WNV infection requires gasdermins or IL-1 receptor expression in hematopoietic cells and MyD88 signaling in myeloid cells. Blocking monocyte trafficking also reduces WNV-induced GI tract permeability and brain inflammation. Finally, WNV infection of mice lacking IFNAR1 only in myeloid cells results in enhanced GI tract and brain inflammation. In the context of attenuated type I IFN signaling, WNV infection in the GI tract results in barrier disruption, inflammasome activation, MyD88-dependent systemic inflammation, and enhanced brain pathogenesis.