Innate Sensing of Viruses by Toll-Like Receptors

The ability to detect pathogens is arguably the single most important task undertaken by the immune system. Appropriate recognition of invasive microbes is critical for mounting an immune response that can effectively combat the invading organism. A comprehensive understanding of the requirements for pathogen recognition is necessary for the development of efficacious vaccines and effective therapeutics. Toward this end, a tremendous investment has been made in determining how the adaptive immune system (B and T cells) distinguishes invading pathogens from host cells and tissues. These efforts have yielded remarkable models that describe how the immune system responds to the myriad of challenges it faces and provide a framework into which future discoveries can be incorporated. Recently, however, some of this focus has been redirected to understanding how pathogens are initially recognized by the host innate immune system and how these events contribute to and coordinate with the adaptive immune response. Detection of pathogens by the innate immune system is carried out by a class of immune-sensor molecules termed pattern recognition receptors, or PRRs. Several different classes of PRRs have been identified, each detecting microbes or microbial components and initiating responses that program antipathogen gene expression profiles and promote adaptive immune responses (28). The Toll-like receptors (TLRs) are a class of PRRs that detect an increasingly broad range of pathogens (74). While the majority of the work on TLRs has focused on detection of bacteria, it is becoming increasingly apparent that viruses are also subject to innate sensing by TLRs. An indicator of the importance of any host antiviral strategy is the ability of viruses to counteract that particular arm of the host defense. Two vaccinia virus genes, A46R and A52R, have been implicated as negative regulators of TLR signaling, indicating that TLR responses pose a realistic threat to viruses (11a, 29a). This review will focus on the state of our knowledge of TLRs' role in immune responses to viruses.