The Protective and Pathologic Roles of Toll-like Receptors in Arthritogenic Alphavirus Infection

Arthritogenic alphaviruses, including Chikungunya virus and Ross River virus (RRV), are mosquito-borne pathogens responsible for epidemics of debilitating polyarthritis in humans. The host inflammatory response plays an important role in the pathogenesis of arthritic alphaviruses, where some pathways, such as the complement cascade, exacerbate virus-induced disease, while type I IFN and other immune signaling pathways mediate protection from disease. Using a mouse model of alphavirus-induced arthritis/myositis, we demonstrated that toll-like receptor (TLR) signaling contributes to protection from and enhancement of alphavirus-induced disease. Myd88-dependent TLR7 signaling was critical for protection from severe RRV-induced morbidity and mortality. Additionally, TLR7 deficiency resulted in the production of low affinity, non-neutralizing RRV-specific antibodies that exacerbated virus-induced disease through systemic antibody- and complement-mediated mechanisms. Furthermore, TLR4 promoted RRV-induced morbidity and tissue damage in a complement-dependent manner, and complement-associated macrophage activation was dependent on TLR4 expression during RRV infection. Taken together, these studies establish the integral role that TLR pathways play in arthritic alphavirus pathogenesis and suggest that designing therapeutic strategies that target TLR signaling may aid in the treatment of RRV infection.Doctor of Philosoph