Toll-like receptors regulation of viral infection and disease

Abstract

In recent years, it has become increasingly evident that mammalian Toll-like receptors (TLRs) play a critical role in determining the outcome of virus infection. TLRs have evolved to recognize viral nucleic acids, and promote the stimulation of innate and adaptive immune responses. Interestingly, the study of mice harboring deficiencies in various TLR proteins and their adaptors suggests that TLR activation promotes protective anti-viral immunity in some cases, while exacerbating virus-induced disease in others. In this report we describe the interactions of viruses with both the TLR system and the intracellular recognition system and highlight the role of TLRs in shaping the outcome of virus infection in both a positive and negative manner.

Figure 1. Positive and negative consequences of TLR-virus interaction

Viral sensing, following either direct fusion with the plasma membrane, or receptor-mediated endocytosis, initiates innate immunity and regulates virus-induced disease. Depending upon the viral genome content and entry mechanism, viral nucleic acids, or replicative intermediates, are recognized by one of the cellular sensing molecules such as DAI, RIG-I/MDA5, or one of the endosomal TLRs (3, 7, 9), and an innate anti-viral program is activated. Recognition of RNA viruses (RIG-I/MDA5) and DNA viruses (DAI) by the intracellular sensors stimulates innate immunity that limits replication and promotes protection. In the case of the TLR pathway, viral sensing by endosomal TLRs may lead to a protective innate and adaptive immune response. For certain ssRNA viruses, the delivery of viral PAMP to the late endosome/lysosome compartment is mediated by autophagy. Conversely, these interactions may exacerbate virus-induced disease, leading to a poor outcome for the host. Likewise, plasma membrane TLRs may also promote virus-induced inflammation. Together, these examples highlight how viral-TLR interactions affect virus-induced disease both in a positive and negative fashion.