The long-term objective of this proposal is to gain insight into the mechanisms of action of the receptor interacting protein 2 (RIP2) in host biodefense against Listeria monocytogenes infection. RIP2 is a member of the RIP family of serine/threonine (Ser/Thr) kinases. It has been implicated in the signal transduction pathways activated by the Nod receptor family proteins, potential receptors for intracellular pathogens. We recently created knockout mice lacking the RIP2 gene, and found that RIP2-/- mice are severely impaired in their ability to defend against infection with L. monocytogenes. Our preliminary results also indicated that RIP2-/- macrophages have lost their ability to respond to muramyl dipeptide (MDP), the minimal immunostimulatory subunit of peptidoglycan from gram positive bacteria. In addition, RIP2-/- T helper 1 (Thl) and natural killer (NK) cells have reduced interferon gamma (IFN-gamma) production upon IL-12 stimulation. We hypothesize that RIP2 may be involved in multiple signaling and cellular events to coordinate innate and adaptive immune responses in host biodefense against pathogen infection. We propose experiments to investigate RIP2- mediated signal transduction pathways and to determine the in vivo role of RIP2 in immune responses during pathogen infections. First, we hypothesize that RIP2 is involved in MDP-induced activation of innate immune responses. We will determine the role and the mechanism of RIP2 in mediating signal transduction and cytokine production by macrophages in response to MDP stimulation. Second, we hypothesize that RIP2 is involved in Thl differentiation by modulating the activity of IL-12-induced STAT4 activation and interferon gamma (IFN-gamma) production. We will first confirm the intrinsic defects of RIP2-/- Thl cells, and then explore potential signaling events where RIP2 might be involved in IL-12-induced STAT4 activation and interferon IFN-(, production. Third, we hypothesize that RIP2 is involved in host defense against microbial infections by affecting both innate and adaptive immune responses. We will determine the susceptibility of RIP2-/- mice to gram-positive and gram-negative extracellular and intracellular bacteria to understand the role of RIP2 in determining the pathogen specificity. We will also use L. monocytogenes infection of RIP2-/- mice as a model to determine the contribution of RIP2 in innate and adaptive immune responses against microbial infections. We believe that the insights obtained from these studies will provide new knowledge about pathogen recognition and coordination between innate and adaptive immune systems, and suggest new avenues of immunologic intervention to prevent and treat many human infectious diseases.
|Atarashi, Koji; Tanoue, Takeshi; Shima, Tatsuichiro et al. (2011) Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331:337-41|
|Pietras, Eric M; Miller, Lloyd S; Johnson, Carl T et al. (2011) A MyD88-dependent IFN?R-CCR2 signaling circuit is required for mobilization of monocytes and host defense against systemic bacterial challenge. Cell Res 21:1068-79|
|Miller, Lloyd S; Pietras, Eric M; Uricchio, Lawrence H et al. (2007) Inflammasome-mediated production of IL-1beta is required for neutrophil recruitment against Staphylococcus aureus in vivo. J Immunol 179:6933-42|
|Miller, Lloyd S; O'Connell, Ryan M; Gutierrez, Miguel A et al. (2006) MyD88 mediates neutrophil recruitment initiated by IL-1R but not TLR2 activation in immunity against Staphylococcus aureus. Immunity 24:79-91|
|O'Connell, Ryan M; Vaidya, Sagar A; Perry, Andrea K et al. (2005) Immune activation of type I IFNs by Listeria monocytogenes occurs independently of TLR4, TLR2, and receptor interacting protein 2 but involves TNFR-associated NF kappa B kinase-binding kinase 1. J Immunol 174:1602-7|