This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Genital herpes caused by both HSV types 1 and 2 remains a common and chronic infection for which there is no effective vaccine. Despite effective HSV antivirals, two disconcerting trends have been observed: 1) the prevalence of genital herpes continues to rise with approximately 1.6 million new cases occurring annually;2) there has been an increased incidence of recurrent genital lesions. These trends are especially alarming considering the role HSV-2 may play in facilitating other STIs. Significantly, HSV-2 genital infection is an important cofactor for HIV acquisition, with statistical modeling attributing almost half of all HIV transmission to HSV-2 infections. HSV-2 infections contribute to increased STIs by either modulating cell-intrinsic innate recognition and response pathways or increasing the inflammatory milieu within the genital tract mucosa. The molecular mechanisms through which HSV-2 impairs the immune response are still poorly understood. Our preliminary studies have recently identified a potential """"""""adaptor"""""""" domain within HSV glycoprotein K (gK) that is able to modulate a cadre of signal transduction pathways involved in innate recognition and response to invading pathogens. We therefore hypothesize that HSV-2 gK protein subverts the innate immune response from a protective response to a chronic inflammatory process that aides the survival of HSV-2 and promotes infections by other infectious agents. We proposed to dissect the mechanisms by which HSV gK suppresses inflammation-associated pathogen recognition and response pathways and thereby promotes the establishment of a persistent lifelong infection. Understanding these mechanisms will provide important information towards the development of new anti-HSV therapies or to the development of an effective vaccine.
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