Endogenous retroviruses activate MARCO-mediated inflammatory response to block retroviral infection

Endogenous retroviruses (ERVs) are remnants of ancient retroviral infections and can profoundly affect the host antiviral innate immune response, although the mechanisms by which these changes occur are largely unknown. Here we report that chicken-specific ERVs exert genetic resistance to exogenous retrovirus infection. Mechanistically, chicken-specific ERVs activated the scavenger receptor MARCO (macrophage receptor with collagenous structure)-mediated TLR3-IL-1β inflammatory response in macrophages. Under the presence of MARCO, macrophages response to viral infection through inducing TLR3-IL-1β inflammatory response. Conversely, lack of MARCO increased the viral replication levels and attenuated the antiviral inflammatory response. MARCO-mediated ligand delivery enhances TLR3-IL-1β antiviral response, and IL-1β expression is responsible for viral inhibition. Restoring MARCO or IL-1β expression overcomes viral infection in macrophages. Our study provides new insights into the molecular mechanisms underlying the host defense against exogenous retroviruses infection and may have important implications for the development of novel therapeutic strategies against retroviruses infection.