KSHV is both a commensal and pathogenic microorganism in the oral mucosa. In most healthy individuals with an intact immune system, KSHV is kept in check and does not cause disease. However in conditions of immune suppression like HIV infection or immunosuppressive therapy, KSHV can cause sarcomas and lymphomas in the oral cavity. Thus KSHV is considered to be an opportunistic oral pathogen. The development of Kaposi's sarcoma is much more frequent in older individuals than in young people. Thus there appears to be an age dependency for the onset of Kaposi's sarcoma. It is currently unclear how the immune system keeps KSHV in check in healthy individuals, but allows disease to progress during times of immune suppresion. It is known that the aging process is associated with increased inflammation but decreased anti-viral responses. Additionally, newborns and children have an increased susceptibility to infectious diseases, and this has been linked both to immaturity of the immune system at birth and to the slow development of immune competence in the postnatal years. This susceptibility to infections is even more increased with respect to intracellular pathogens, reflecting the functional immaturity of cell-mediated immunity. Toll-like receptors (TLRs) are a very important means by which the innate immune system recognizes microbial pathogens like KSHV. TLR activation needs a slew of intracellular players that interact with the TLRs, including MyD88, TRAFG, and RIP2. In addition, our collaborator, Dr. Ting, first described the CATERPILLER (CLR) protein family. These proteins play both positive and negative roles in the regulation of innate immunity in response to pathogens. and are considered as intracellular sensors of pathogens. In response to RFA-DE-07-004, we propose to understand how the innate immune system recognizes KSHV and the signaling pathways that are induced by the Toll-like receptors in response to KSHV infection during ontogeny. We hypothesize that activation of TLR signaling pathways by KSHV in cells from neonates and old individuals is blunted as compared to the signaling response in cells from young adults. We also propose to understand the roles of TLRs, their cellular adaptors, and the CLR proteins in KSHV infection durirlg ontogeny.
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