The mammalian innate immunity is the first line of the host defense against invading pathogens including viruses. Within the host, antigen-presenting cells such as dendritic cells and macrophages, express a variety of pattern recognition receptors (PRRs) that recognize specific pathogen-associated molecular patterns (PAMPs) within microbial structures such as nucleic acid. Signaling via PRRs leads to the production of a variety of cytokines including proinflammatory cytokines, interferons (IFNs) and chemokines to control viral replication and spread. The mammalian Toll-like receptors (Tlrs) that consist of more than ten members are curial for the recognition of a variety of PAMPs. West Nile virus (WNV), which has caused severe morbidity and mortality in humans and animals in North American, is a single-stranded RNA virus that can be recognized by Tlr7. Our preliminary studies demonstrated that Tlr7 deficient (Tlr7-/-) mice increase susceptibility to WNV infection. Moreover, we found that Tlr7-/- immune cells (leukocytes and macrophages) fail to home to WNV infected cells in brain and liver, which likely explains why Tlr7-/- mice increase death upon WNV infection. In addition, chemokine and cytokine array analysis showed that interleukin-12/23p40 (IL-12/23p40) expression was reduced in macrophages and plasma of Tlr7-/- mice. Furthermore, IL-23 but not IL-12 was found to be able to attract wild-type macrophages migration in vitro. In this proposed project, we will dissect the mechanisms underlying Tlr7-mediated immune cell migration to combat WNV infection.
Specific Aim 1 : Further delineate expression of IL-23 and its receptors in Tlr7 -/- mice after WNV infection.
Specific Aim 2 : Determine whether IL-23-/- mice are deficient in immune cell infiltration and homing after WNV infection. This project will not only expand our understanding of Tlr7 - IL-23 signaling pathway in control of WNV encephalitis, but may result in new therapeutics against WNV infection.
This project is to dissect the mechanisms underlying Toll-like Receptor 7- mediated immune cell infiltration and homing to combat West Nile virus infection in the murine model of West Nile virus encephalitis.
| Wang, Penghua; Yang, Long; Cheng, Gong et al. (2013) UBXN1 interferes with Rig-I-like receptor-mediated antiviral immune response by targeting MAVS. Cell Rep 3:1057-70 |
| Wang, Penghua; Bai, Fengwei; Zenewicz, Lauren A et al. (2012) IL-22 signaling contributes to West Nile encephalitis pathogenesis. PLoS One 7:e44153 |
| Bai, Fengwei; Kong, Kok-Fai; Dai, Jianfeng et al. (2010) A paradoxical role for neutrophils in the pathogenesis of West Nile virus. J Infect Dis 202:1804-12 |
