Role of a Novel Toll-like Receptor in Response to Viral Infection

Texas A&M University Health Science Ctr, College Station TX

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Abstract

Toll-like receptors (TLRs), the key molecular sensors used by the mammalian innate immune system to detect microorganisms, were identified only in the late 1990s. These evolutionarily conserved receptors recognize pathogen associate molecular patterns (PAMPs), and their activation leads to an appropriate host-defense response. Tremendous progress has been made over the past few years in determining the role of TLRs in innate immunity. However we are still in an exponential phase of discovery about many important aspects of TLR biology. We have recently cloned a novel member of the mammalian Toll-like receptor (TLR) family, TLR13. This receptor is predominately expressed in dendritic cells. TLR13 appears to activate a TLR signaling pathway inducing the activation of not only NF-κB but also type 1 interferon. Remarkably, TLR13 seems to be an intracellular TLR and is involved in the recognition of respiratory syncytial virus. We therefore hypothesize that TLR13 represents a novel member of the TLR family that plays a role in the recognition of viral infection to activate innate immune responses. We are proposing to characterize the biological and molecular role of TLR13 using a combination of genetic, molecular and biochemical approaches. Generated specific antibodies against TLR13 will be used to determine the endogenous protein localization. We will study the pattern of expression of TLR13 and determine whether its cellular localization and level of expression are altered upon stimulation of cells with viruses as well as other inflammatory mediators. Then we will determine whether TLR13 is able to cooperate with other members of the TLR family. Identification of TLR13-specific ligand will be performed using biochemical and genetic approaches. Furthermore, we will determine the signaling pathways activated by TLR13. Finally, a TLR13 knock-out mouse model will be generated to systematically analyze the biological role of TLR13. Characterization of TLR13 and identification of its specific ligand may provide the opportunity to create a novel vaccination strategy against viral infection in the future.