The ability of a host to sense invasion by pathogenic organisms and respond appropriately to control infection is paramount to survival. In some cases, however, an exaggerated inflammatory response can lead to bystander injury and systemic inflammatory symptoms, possibly contributing to the morbidity and mortality associated with overwhelming infections. The pro-inflammatory cytokine interleukin (IL)-1 is a critical mediator of host defense against a variety of infectious states. For example, IL-1 is produced in the lung after intratracheal administration of lipopolysaccharide, and its presence is directly associated with lung inflammation and bacterial burden in pneumonia. IL-1 is required for control of a variety of intracellular pathogens, such as Listeria, Leishmania, and Mycobacterium tuberculosis. However, little is known about the role of IL-1 in control of Chlamydophila pneumoniae, an obligate intracellular bacteria that is associated with a variety of acute infectious processes, such as atypical pneumonia, bronchitis, and pharyngitis;chronic infection with C. pneumoniae has also been linked to a variety of chronic inflammatory states, including atherosclerosis. The central hypothesis of this proposal is that C. pneumoniae-induced IL-1? plays contradictory roles in the defense of acute vs. chronic infections. Our preliminary data demonstrates that C. pneumoniae, unlike other related chlamydia species, has the unique ability to directly induce IL-1? secretion from murine bone marrow derived macrophages, and that this induction is dependent on the NALP3/ASC inflammasome complex. We believe that while IL-1? plays an important role in resolution of acute pneumonia, its induction in the setting of chronic infection contributes to the inflammation that is characteristic of atherosclerotic plaque formation. To further understand the role of C. pneumoniae-induced IL-1? in the development of disease, we propose the following Specific Aims: (1) To define the molecular mechanism behind the induction of IL-1? by macrophages infected with C. pneumoniae;(2) To examine the role IL-1? and the IL-1 receptor in acute bacterial pneumonia and the systemic inflammatory response;and (3) To examine the role IL-1? and the IL-1 receptor in the chronic inflammatory plaque formation that is characteristic of atherosclerosis.

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The immune response requires a fine balance between protection against the danger posed by invading microorganisms, and prevention of collateral damage to normal tissue. The long-term goals of this project are to determine how signaling by the cytokine IL-1 is involved in generating the inflammatory response to both acute and chronic infections with C. pneumoniae, and to determine the role of pro-inflammatory cytokine IL-1 in mediating both the protective immune response and the complications associated with it.

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Boston University
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