Tolls: you pay them on the way in and on the way out!

Toll-like receptors (TLRs) are important components of the innate immune system , the evolutionary ancient response system consisting of pattern recognition proteins that recognize pathogen associated molecular patterns (PAMPs). TLRs are a series (10 in humans) of cell surface or intracellular receptor proteins that contain signaling motifs that are structurally similar to the mammalian interleukin (IL)–1 receptor and the Toll protein of insects. In mammals, TLRs function by recognizing viruses, bacteria, fungi, and parasites on the basis of their PAMPs, and then activating cells to produce cytokines including interferon (IFN) and inflam-matory cytokines such as IL-1 and tumor necrosis factor that may either lead to local or systemic inflammation (reviewed in [1]). TLRs also activate the adaptive immune responses (B and T cells). As a result , they are critical to the initial host response to infection. TLR4 was originally described as the cell surface receptor that signaled the binding of lipopolysaccharide and was therefore responsible for septic shock after infection with gram-negative organisms. TLR2 was initially shown to be important in the sepsis syndrome caused by gram-positive organisms. In this issue of the Journal, Bochud et al. [2] have noted an association between polymorphisms in TLR2 and recurrences of herpes simplex virus type 2 (HSV-2) infection. This type of study brings us closer to understanding how genetic predispositions define how one will respond to an infectious challenge. If, in the future, we can use genetic polymorphisms to predict responses to pathogens, this would help in understanding and therefore potentially altering the course of an infectious disease. The concept that one could predict an individual's response to an infectious agent on the basis of his/her genetic predisposition is the " holy grail " of molecular genetics. If this is correct, it opens the door to new diagnostic and therapeutic approaches. For example, one might selectively vaccinate those who are likely to develop overwhelming disease to try to shift their im-munologic profile from a Th2 response pattern (characterized by high levels of an-tibodies and IL-10 production) to a Th1 response (characterized by cytolytic T cell responses and IFN-g production). A particular TLR polymorphism might predict an inability to respond to a conventional dose of vaccine and mandate a different approach (perhaps the use of an adjuvant or another approach to prevention). The interesting question is, " how does a polymorphism in a pattern recognition protein affect the pathogenesis of an infectious …