The role of toll -like receptors 3 and 4 in pulmonary vaccinia infection.

Abstract

Toll-like receptors (TLR) are important detectors of microbial infections, signaling in response to pathogen-associated molecular patterns to activate innate immunity and regulate adaptive immune responses. Toll-like receptor 3 (TLR3) detects double-stranded RNA, while toll-like receptor 4 (TLR4) is characterized as a receptor for bacterial lipopolysaccharide (LPS). Vaccina is an orthopoxvirus, closely related to <italic>Variola major</italic>, for which it is a model and a vaccine. Concerns about bioterrorism and about the safety of the current smallpox vaccine have renewed interest in understanding the molecular basis for the immune response to poxviruses. This research uses a mouse model to investigate roles played by TLR3 and TLR4 in response to vaccinia infection. We show that TLR3 signaling initiates an inflammatory response that, through systemic cytokine release, both increases morbidity and mortality and permits increased viral replication. We also establish that TLR4 signals in response to vaccinia infection, but signaling through this receptor is protective. TLR4 limits viral replication and inflammation. These findings provide new information about functions of TLRs in viral infection. They reveal the immunopathogenic role of the inflammatory response to poxviral infection, and highlight the complexity of TLR effects. Antagonizing the TLR3 response and enhancing TLR4 may be a strategic approach to vaccine and drug design.