The opportunistic pathogen, Pneumocystis carinii, colonizes the alveolar epithelium of individuals suffering from a variety of conditions that affect CD4+ T cell number and/or function, including AIDS patients. Although no reliable culture system exists for the direct study of P. carinii organisms, there are good animal models of infection that closely mimic the human disease. In our laboratory, we study two mouse models of P. carinii pneumonia (PcP) that approximate clinical presentations of PcP in patient populations. The CD4+ T cell-depleted model of PcP serves as a model of chronic P. carinii infection in AIDS patients. We have recently demonstrated that in the absence of CD4+ T cells, a chronic CD8+ T cell-mediated inflammatory response is mounted against P. carinii. Although this response cannot protect against infection, it does contribute significantly to lung injury and respiratory impairment. In addition, we also study an immune-reconstituted SCID mouse model of PcP. This is a more acute, fulminant onset form of the disease, and serves as a good model of the increasingly recognized syndrome of P. carinii-related immunorestitution disease in humans. These patients undergo a period of significant immunosuppression, when they develop subclinical P. carinii infection, followed by recovery of cell-mediated immunity. Subsequently, an intense inflammatory response is mounted against the pre-existing infection. Recently, we have demonstrated that the degree of pulmonary inflammation induced by the pre-existing P. carinii infection is the critical determinant in the level of respiratory impairment observed, while the organism produces little direct injury. Thus, the burden of P. carinii is not the critical factor, but the ability of the host to mount an inflammatory response is directly relevant to disease outcome.

Presently, we are performing studies aimed at identifying specific mechanisms of inflammation-related injury that contribute to the pathology of PCP in the two mouse models of infection described above. We perform physiological and molecular measurements of lung injury to assess the in vivo contribution of specific cell populations and inflammatory mediators to the pathophysiology of PcP. These studies will help define the role of pulmonary inflammation during PCP, and may identify important targets of immune therapy for the prevention of inflammatory component of PcP-associated lung injury.

Wright TW, Pryhuber GS, Chess PR, Wang Z, Notter RH, Gigliotti F. TNF receptor signaling contributes to chemokine secretion, inflammation, and respiratory deficits during Pneumocystis pneumonia. J Immunol. 172:2511-21, 2004.

Gigliotti F, Harmsen AG, Wright TW. Characterization of transmission of Pneumocystis carinii f. sp. muris through immunocompetent BALB/c mice. Infect Immun. 71:3852-6, 2003.

Staversky RJ, Watkins RH, Wright TW, Hernady E, LoMonaco MB, D'Angio CT, Williams JP, Maniscalco WM, O'Reilly MA. Normal remodeling of the oxygen-injured lung requires the cyclin-dependent kinase inhibitor p21(Cip1/WAF1/Sdi1). Am J Pathol. 161:1383-93, 2002.

Gigliotti F, Haidaris CG, Wright TW, Harmsen AG. Passive intranasal monoclonal antibody prophylaxis against murine Pneumocystis carinii pneumonia. Infect Immun. 70:1069-74, 2002.

Wright TW, Notter RH, Wang Z, Harmsen AG, Gigliotti F. Pulmonary inflammation disrupts surfactant function during Pneumocystis carinii pneumonia. Infect Immun. 69:758-64, 2001.

Lee LH, Gigliotti F, Wright TW, Simpson-Haidaris PJ, Weinberg GA, Haidaris CG. Molecular characterization of KEX1, a kexin-like protease in mouse Pneumocystis carinii. Gene. 242:141-50, 2000.

Wright TW, Gigliotti F, Finkelstein JN, McBride JT, An CL, Harmsen AG. Immune-mediated inflammation directly impairs pulmonary function, contributing to the pathogenesis of Pneumocystis carinii pneumonia. J Clin Invest. 104:1307-17, 1999.

Wright TW, Johnston CJ, Harmsen AG, Finkelstein JN. Chemokine gene expression during Pneumocystis carinii-driven pulmonary inflammation. Infect Immun 167:3452-3460, 1999.