Many pathogens use the intestinal mucosa as the primary site of entry. The intestinal mucosa must induce a rapid and strong immune response to defend against such pathogenic invasion, yet an excessive immune response to commensal flora leads to chronic inflammation like inflammatory bowel disease. While it is evident that mucosal antigen-presenting cells (APCs) play a key role in orchestrating the effector response to pathogens, it is unclear how APCs maintain homeostasis with commensals. At the initiation of an immune response, mucosal APCs sense pathogens by using toll- like receptors (TLRs) that in turn signal through the adapter molecules MyD88 (myeloid differentiation factor 88) or TRIF (Toll/interleukin-1 receptor domain-containing adapter inducing IFN-?). Most research has focused on the MyD88 pathway because it is used by almost all TLRs and it leads to a robust NF-?B response. However, strong NF-?B activation may also destroy host tissues. By contrast, the TRIF pathway is only induced by TLR4 or TLR3 and supports regulatory responses through induction of IFN?. Therefore, there must be unique roles of TRIF pathway in intestinal immune regulations, but how this pathway contributes to host defense against intestinal bacterial infection has not been studied. Our ultimate goal is to protect the intestinal mucosa from infection and chronic inflammation through the future development of vaccines and immunotherapies. But fundamental research is needed to understand specific aspects of TLR signaling in the intestinal mucosa to achieve this goal. The objective of this application is to understand how APCs regulate intestinal immune responses through TRIF signaling. We wish to test the hypothesis that TRIF signaling in APCs regulates protective immune responses in the intestine. Using Yersinia enterocolitica as a model enteric pathogen, we found that TRIF-deficient mice had a significant defect in macrophage bactericidal activity. They succumb to infection due to systemic Y. enterocolitica dissemination. These findings lead us to examine how TRIF signaling in APCs regulates intestinal immune responses during bacterial infection. Once the mechanism of TRIF-mediated immune defense is elucidated, this signaling can be pharmacologically manipulated leading to innovative approaches in the management of inflammatory and infectious diseases affecting the intestine. Targeting TRIF is advantageous because a clinically tested TLR3 ligand is available.
The intestinal mucosa must induce rapid and strong immune responses to defend against food poisoning germs, yet too much immune response to normal intestinal flora leads to serious chronic colitis. Based on our findings, we focus on a certain molecule of the immune system that may have protective effect on intestinal infection and chronic colitis. The accomplishment of this project will identify an important immune regulator that can apply a novel treatment strategy for a variety of intestinal diseases.
|Kanagavelu, Saravana; Flores, Claudia; Hagiwara, Shinichiro et al. (2016) TIR-Domain-Containing Adapter-Inducing Interferon-? (TRIF) Regulates CXCR5+ T helper Cells in the Intestine. J Clin Cell Immunol 7:|
|Kanagavelu, S; Flores, C; Termini, J M et al. (2015) TIR-domain-containing adapter-inducing interferon-? (TRIF) regulates Th17-mediated intestinal immunopathology in colitis. Mucosal Immunol 8:296-306|
|Hyun, Jinhee; Romero, Laura; Riveron, Reldy et al. (2015) Human intestinal epithelial cells express interleukin-10 through Toll-like receptor 4-mediated epithelial-macrophage crosstalk. J Innate Immun 7:87-101|
|Ruiz, Jose; Kanagavelu, Saravana; Flores, Claudia et al. (2015) Systemic Activation of TLR3-Dependent TRIF Signaling Confers Host Defense against Gram-Negative Bacteria in the Intestine. Front Cell Infect Microbiol 5:105|
|Kanagavelu, Saravana; Flores, Claudia; Termini, J M et al. (2015) TIR Domain-Containing Adapter-Inducing Beta Interferon (TRIF) Mediates Immunological Memory against Bacterial Pathogens. Infect Immun 83:4404-15|
|Siefker, David T; Echeverry, Andrea; Brambilla, Roberta et al. (2014) Murine neonates infected with Yersinia enterocolitica develop rapid and robust proinflammatory responses in intestinal lymphoid tissues. Infect Immun 82:762-72|
|Fukata, M; Arditi, M (2013) The role of pattern recognition receptors in intestinal inflammation. Mucosal Immunol 6:451-63|
|Hyun, Jinhee; Kanagavelu, Saravana; Fukata, Masayuki (2013) A unique host defense pathway: TRIF mediates both antiviral and antibacterial immune responses. Microbes Infect 15:1-10|
|Sotolongo, John; Kanagavelu, Saravana; Hyun, Jinhee et al. (2012) TRIF mobilizes unique primary defense against Gram-negative bacteria in intestinal interface. Gut Microbes 3:437-41|