HEITMAN J; Interscience Conference on Antimicrobial Agents and Chemotherapy (43rd: 2003: Chicago, Ill.).

Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother. 2003 Sep 14-17; 43: abstract no. 1139.

Duke Univ. Med. Ctr., Durham, NC.

The incidence of fungal infection is increasing and yet available antifungal drugs are limited, some are toxic, and drug resistant strains are emerging.We have elucidated a conserved signal transduction cascade that controls virulence of Cryptococcus neoformans, the leading cause of fungal meningitis. The central element of this virulence pathway is the calcium-calmodulin activated protein phosphatase calcineurin, which is the molecular target of the immunosuppressive antifungal drugs cyclosporin A and FK506. C. neoformans mutants lacking either the catalytic A or the regulatory B subunit of calcineurin are inviable at 37degreesC and other stress conditions and, as a consequence, are avirulent in animal models. In recent studies we identified: 1) the calcineurin B regulatory subunit and calmodulin, 2) the calcineurin binding protein (Cbp1) that is a conserved regulator or effector and the founding member of a protein family conserved from fungi to humans, and 3) the novel C2 domain protein Cts1 that functions coordinately with the calcineurin signaling pathway to promote cell wall biogenesis and growth at 37degreesC. In parallel we discovered that calcineurin is required for virulence of Candida albicans, the most common human fungal pathogen. C. albicans cnb1/cnb1 mutants lacking the calcineurin B regulatory subunit are severely attenuated in animal models. Yet, in contrast to C. neoformans calcineurin is not required for growth of C. albicans at 37degreesC. Instead, calcineurin is necessary for C. albicans to survive and proliferate in serum. These studies illustrate how a conserved signaling cascade has been co-opted to control virulence of two divergent fungal pathogens by unique molecular mechanisms. Importantly, this pathway can be targeted for therapeutic intervention using non-immunosuppressive calcineurin inhibitors that retain antifungal activity and synergistic drug combinations. References: [1] Fox, D.S., Cruz, M.C., Sia, R.A.L., Ke, H., Cox, G.M., Cardenas, M.E., and Heitman, J. Calcineurin regulatory subunit is essential for virulence and mediates interactions with FKBP12-FK506 in Cryptococcus neoformans. Mol. Microbiol., 39: 835-849, 2001. [2] Cruz, M.C., Goldstein, A.L., Blankenship, J.R., Davis, D., Del Poeta, M., Cardenas, M.E., Perfect, J.R., McCusker, J.H., and Heitman, J. Calcineurin is essential for survival during membrane stress in Candida albicans. EMBO J., 21: 546-559, 2002. [3] Blankenship, J.R., Steinbach, W.J., Perfect, J.R., and Heitman, J. Teaching old drugs new tricks: reincarnating immunosuppressants as antifungal drugs. Current Opinion in Investigational Drugs, 4: 192-199, 2003. [4] Kraus, P.R., Fox, D.S., Cox, G.M., and Heitman, J. The C. neoformans MAP kinase homolog Mpk1 regulates cell integrity in response to antifungal drugs and loss of calcineurin function. Mol. Micro, 48: 1377-87, 2003. [5] Blankenship, J.R., Wormley, F.L., Boyce, M.K., Schell, W.A., Filler, S.G., Perfect, J.R., and Heitman, J. Calcineurin is essential for Candida albicans survival in serum and virulence, Euk. Cell, 2: 422-430, 2003. heitm001@duke.edu

Publication Types:

• Meeting Abstracts

Keywords:

• Antifungal Agents
• Calcineurin
• Candida albicans
• Cell Wall
• Cryptococcosis
• Cryptococcus neoformans
• Cyclosporine
• Humans
• Immunosuppressive Agents
• Phosphoprotein Phosphatases
• Tacrolimus
• Tacrolimus Binding Protein 1A
• Virulence
• pathogenicity

Other ID:

• GWAIDS0025857

UI: 102265481

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