Pneumocystis is an opportunistic fungal pathogen which causes severe pneumonia (PCP) in patients with AIDS. During pneumonia, Pneumocystis proliferates through trophic forms and cysts. Mechanisms regulating the Pneumocystis life cycle are not well defined, however a pheromone-induced mitogen-activated protein kinase (MAPK) signaling pathway regulates this process in closely-related fungi. Our studies demonstrate that the P. carinii MAPK PCM, an ortholog to fungal pheromone MAPKs, complements pheromone signaling in yeast. PCM expression and activity are greatly augmented in trophic forms compared to cysts, implicating PCM activity in Pneumocystis life cycle transition. We have discovered that PCM has unique requirements for biochemical kinase activity, and the typical phosphorylation sites required for MAPK function are not needed for PCM kinase activity. These findings suggest novel regulation of PCM, the further study of which might provide insights into signaling pathways hi pathogenic fungi. Additionally, we have identified putative pheromone receptors and a transcription factor as part of this MAPK pathway in P. carinii. In the current proposal, we hypothesize that the pheromone-induced mitogen-activated protein kinase (MAPK) pathway regulates cellular differentiation and proliferation of P. carinii. We will investigate these concepts through three independent but interrelated Specific Aims. Through these investigations we hope to gain insights into P. carinii biology which may provide new information for novel drug development to treat PCP.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
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Duncan, Rory A
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Mayo Clinic, Rochester
United States
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Vohra, Pawan K; Park, John G; Sanyal, Bharati et al. (2004) Expression analysis of PCSTE3, a putative pheromone receptor from the lung pathogenic fungus Pneumocystis carinii. Biochem Biophys Res Commun 319:193-9
Vohra, Pawan K; Sanyal, Bharati; Thomas Jr, Charles F (2004) Biochemical requirements for PCBCK1 kinase activity, the Pneumocystis carinii MEKK involved in cell wall integrity. FEMS Microbiol Lett 235:153-6
Thomas Jr, Charles F; Limper, Andrew H (2004) Pneumocystis pneumonia. N Engl J Med 350:2487-98
Vohra, Pawan K; Puri, Veenu; Kottom, Theodore J et al. (2003) Pneumocystis carinii STE11, an HMG-box protein, is phosphorylated by the mitogen activated protein kinase PCM. Gene 312:173-9
Morales, Ian J; Vohra, Pawan K; Puri, Veenu et al. (2003) Characterization of a lanosterol 14 alpha-demethylase from Pneumocystis carinii. Am J Respir Cell Mol Biol 29:232-8
Vohra, Pawan K; Kottom, Theodore J; Limper, Andrew H et al. (2003) Pneumocystis carinii BCK1 complements the Saccharomyces cerevisiae cell wall integrity pathway. J Eukaryot Microbiol 50 Suppl:676-7
Thomas Jr, Charles F; Vohra, Pawan K; Park, John G et al. (2003) Pneumocystis carinii BCK1 functions in a mitogen-activated protein kinase cascade regulating fungal cell-wall assembly. FEBS Lett 548:59-68
Vohra, Pawan K; Puri, Veenu; Thomas Jr, Charles F (2003) Complementation and characterization of the Pneumocystis carinii MAPK, PCM. FEBS Lett 551:139-46
Vohra, Pawan K; Thomas Jr, Charles F (2003) Complementation and in vivo biochemical characterization of the Pneumocystis carinii MAPK. J Eukaryot Microbiol 50 Suppl:674-5