P CARINII-EPITHELIAL INTERACTIONS MEDIATE INFLAMMATION

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Pneumocystis carinii produces life-threatening pneumonia (PCP) in immunocompromised patients. Importantly, the clinical severity of PCP often correlates more closely with a patient's ability to mount an inflammatory response against P. carinii than with organism burdens. Alveolar epithelial cells (AECs) interact closely with P. carinii, and the important role of these cells in initiating inflammatory responses is becoming increasingly recognized. The hypothesis of this proposal is that AECs play a critical role in the initial detection and recognition of P. carinii in the alveolar compartment, and that the interaction of P. carinii with the alveolar epithelium stimulates chemokine secretion, and signals the recruitment of inflammatory cells specifically to sites of infection. When immune function is restored to P. carinii-infected SCID mice, T lymphocytes and macrophages are recruited only to sites of infection. In addition to clearing infection, this inflammatory response also results in "bystander" injury to the lung. Our preliminary data extends these observations by demonstrating that beta-chemokines and the beta-chemokine receptors CCR1 and CCR2 are highly expressed in vivo after reconstitution of infected SCID mice, and after inoculation of immunocompetent mice. In addition, we show that the specific attachment of P. carinii to AECs, in vitro, simulates the secretion of TNF-alpha and beta-chemokine gene expression. The specific aims of this proposal are designed to: 1) characterize the ability of P. carinii stimulated AECs to secrete chemokines, and induce the chemotaxis of CD4+ T cells. 2) determine whether CD4+ T cells are required for the early chemokine signals at the alveolar surface following in vivo exposure to P. carinii. 3) determine the role of beta-chemokines in cell recruitment and in resistance to P. carinii by utilizing CCR1 and 2 knockout mice. 4) determine the role of CCR1 and CCR2 in T cell recruitment, organism clearance, and lung injury in a well-characterized model of P. carinii-induced pulmonary inflammation. The goal of this proposal is to understand the inflammatory response to P. carinii so that strategies may be developed to circumvent the lung injury that results from the host response to P. carinii.