Tlr3

The innate immune system is the first line of defense against virus infection and involves the release of proinflammatory cytokines, type I IFNs, and activation of adaptive immune responses. A number of viral products are sensed by cells of the innate immune system; among them, dsRNA is a common signature of viral replication and is generated in infected cells by most (if not all) viruses. In 2001, it was described for the first time that TLR3 mediates responses to poly (I:C), a synthetic analog of dsRNA. Indeed TLR3 knockout mice were resistant to poly (I:C)-induced shock compared to wild-type mice (Alexopoulou et al. 2001). Since the inhibition of endosomal acidification abrogates poly (I:C) signaling, it has been assumed that TLR3 is localized to the endosomal compartment. In fact, TLR3 has been shown to reside in multive-sicular bodies, a subcellular compartment situated in the endocytic trafficking pathway in dendritic cells (DC) and could not be detected on the cell surface (Matsumoto et al. 2003). This intracellular localization of TLR3 is thought to be important for encountering dsRNA.

TLR3 has been implicated in the immune response to several viruses. TLR3 controls inflammatory cytokine and chemokine production in respiratory syncytial virus (RSV)-infected cells (Rudd et al. 2005). RSV-induced CXCL10 and

CCL5 production, but not CXCL8 production or viral replication, were shown to be impaired in the absence of TLR3. Hoebe et al. reported that mice homozygous for the Lps2 mutation, a distal frameshift error in TRIF, are hyper-susceptible to mouse cytomegalovirus (MCMV) (Hoebe et al. 2003), and a role for TLR3 in the response to MCMV was confirmed using TLR3 knockout mice (Tabeta et al. 2004). A major function for TLR3 in antiviral responses involves its role in promoting the cross-priming of cytotoxic T lymphocytes (CTLs). This occurs in cells that are themselves not directly infected. Murine CD8a+ DCs can be activated in this manner by dsRNA present in virally infected cells taken up by phagocytosis (Schulz et al. 2005). These observations may explain the subcellular localization pattern of TLR3 in the endosomal compartment.

In some circumstances, the TLR3-mediated response can be detrimental to the host. During infection with West Nile Virus (WNV), a mosquito-borne ssRNA flavivirus, TLR3-deficient mice were found to be more resistant to lethal WNV infection. TLR3-deficient mice had increased viral load in the periphery (Wang et al. 2004). TLR3-dependent inflammatory response modulates the ability of WNV to invade the central nervous system after replicating in the periphery by inducing a reversible breakdown of the blood-brain barrier. TLR3 knockout mice also have an unexpected advantage upon influenza A virus challenge: a reduction in TLR3-mediated inflammatory response reduces the clinical manifestation of the influenza A-induced pneumonia (Le Goffic et al. 2006). In both of these cases, the virus appears to benefit from its interaction with TLR3.

In addition to viral RNA, heterologous RNA released from or associated with necrotic cells, likely through secondary structure, also stimulates TLR3 and induces immune activation (Kariko et al. 2004). Thus, RNA escaping from damaged tissues or contained within endocytosed cells could serve endogenous danger signals and be sensed by TLR3.

Was this article helpful?

0 0
How To Bolster Your Immune System

How To Bolster Your Immune System

All Natural Immune Boosters Proven To Fight Infection, Disease And More. Discover A Natural, Safe Effective Way To Boost Your Immune System Using Ingredients From Your Kitchen Cupboard. The only common sense, no holds barred guide to hit the market today no gimmicks, no pills, just old fashioned common sense remedies to cure colds, influenza, viral infections and more.

Get My Free Audio Book


Post a comment