Protective immune responses to bacterial infection are triggered by pathogen derived proteins, DNA and lipid components which trigger a diverse array of activation signals. Upon activation, the host inflammatory cells respond to the pathogen-derived insult by the production of inflammatory cytokines and the generation of both reactive oxygen and nitrogen sJDecies (ROS/RNS) that are the cytotoxic effector molecules of the innate immune response. Many pathogens resist the production of macrophage (M0)-derived ROS/RNS by augmenting their ability to detoxify these species or by short circuiting the signaling pathways that lead to their production. A pathogens antioxidant armature not only provides direct protection from oxidative attack, but may interfere with host cell signaling that facilitates its intracellular survival by restricting both the effector and inductive mechanisms responsible for protective immunity. These unique features have led us to develop a hypothesis that links the efficient ROS/RNS scavenging capacity of Francisella tularensis (Ft) SchuS4 to its ability to restrict M0 activity. The end result is the creation of an intraM0 environment that is permissive for growth and subsequent systemic dissemination of this category A pathogen. The underiying hypothesis is that F. tularensis modulates the intracellular redox environment to control M0 signaling and function. We will:
Aim 1. Investigate how Ft antioxidant defenses contribute to its effective growth and intracellular survival both in vitro and in vivo.
Aim 2. Determine the role of Ft SchuS4 antioxidants in regulating M0 function directly or when targeted via FcR.
Aim 3. Determine the redox-sensitive signaling molecules that are responsible for the control of M0 kinase signaling upon infection with FcR-targeted or non-targeted Ft. The studies outlined will not only decipher the redox-triggers that control Ft virulence but also synergize with the overall P01 by developing tools that enable subprojects 1 &2 to evaluate the contribution Ft SchuS4 antioxidants in modulating FcR-specific signals, and TLR/NLR engagement, respectively. By identifying the bacterial redox-factors that mocjulate host immune function we can develop immunogens to optimize mucosal vaccination platform.
Our studies suggest that F. tularensis (Ft) the causative agent of tularemia uses a unique system of antioxidants to resist the host immune system. Our studies merge the expertise of scientists in the fields of free radical biology, bacteriology and immunology to identify new targets for preventative and therapeutic interventions that will be of particular importance to those individuals exposed to Ft naturally or through an act of bioterrorism.
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