Clearance of intracellular bacterial pathogens requires initiation of an effective immune response. However, pathogens have evolved virulence factors to disable such immune responses. A key gap in our knowledge is to understand how successful host defense can be achieved despite pathogen subversion. Legionella pneumophila, an important cause of community- and hospital-acquired pneumonia, disarms and replicates within alveolar macrophages by delivering bacterial effectors via a type IV secretion system (T4SS). Several T4SS effectors potently block host protein synthesis. However, host sensing of Legionella T4SS-translocated substrates paradoxically enhances cytokine production. To elucidate the molecular and cellular basis of this host response, we developed a powerful approach to simultaneously track bacterial effector translocation and cytokine responses at the single cell level. We found that infected cells poorly produced several key cytokines, but could still synthesize and release IL-1 family cytokines. Moreover, IL-1 signaling was required for robust production of cytokines by uninfected immune cells and neutrophil-attracting chemokines by lung epithelial cells. Our findings indicate that paracrine IL-1 signaling circumvents the pathogen-imposed translational block to orchestrate a rapid immune response by uninfected bystander cells. While IL-1 signaling is critical for the initiation of host defense,the cell types responding to IL-1 and the specific consequences of IL-1? and IL-1? responses in these cells are unclear. Moreover, mice lacking IL-1 signaling eventually recover bystander cytokine responses, neutrophil recruitment, and control over infection, suggesting that IL-1-independent immune signals coordinate an additional layer of host defense. Thus, we propose the following Aims to define how IL-1-dependent and IL-1-independent immune mechanisms collaborate to generate successful immunity.
In Aim 1, we will test the hypothesis that IL-1? and IL-1? regulate distinct immune functions in different cell types.
In Aim 2, we will test the hypothesis that additional IL-1-independent immune signals ensure bystander cytokine production and neutrophil recruitment at later stages of Legionella infection. Together, these studies will define novel innate immune mechanisms employed by the host to surmount pathogen-encoded virulence activities. The proposed research will therefore provide vital insight into mechanisms of host defense that are utilized against broad classes of microbial pathogens and aid development of improved anti-microbial therapeutics and vaccines.
The intracellular bacterial pathogen Legionella pneumophila is an important cause of nosocomial and community-acquired pneumonia. We propose to define the mechanisms underlying how the innate immune system successfully overcomes the ability of Legionella to disarm alveolar macrophage function. Defining these mechanisms will enable the design of new anti-bacterial therapeutics that is effective against Legionella and other intracellular bacterial pathogens.
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