Cryptococcus neoformans is a major pathogen in immunocompetant as well as immunocompromised patients including those with AIDS in both the developed as well as the developing world. Our long-term objective is to test the hypothesis that molecular regulators of the virulence factor laccase affect the virulence of Cryptococcus neoformans. 1) Vad1 is an important regulator of mRNA stability in the fungus and had previously been shown to regulate the Mata pheromone involved in mating. During the 2014 period, we demonstrated a role for Vad1 in the regulation of autophagy by its role in modulating mRNA stability of several autophagy-dependent transcripts, extending this work to S. cerevisiae, mouse and human systems. We have also developed antibody reagents that link the target of rapamycin-dependent regulation of autophagy to this novel regulatory pathway. 2) In our work at discovering new regulators of virulence, we identified an extracellular lactonohydrolase (encoded by the LHC1 gene) that was found to modulate higher order structure of the cryptococcal capsule. This is the first description of such extracellular modification of capsule structure in a pathogen. The modification results in a more compressed capsular structure that excludes host molecules such as complement and antibody that normally are effective against invading pathogens, providing new insights as to the effectiveness of this fungal pathogen. 3) In the developing world, a lack of effective fungicidal agents currently results in over 50% mortality in cryptococcosis even after therapy. The only agent available is amphotericin, which was developed in the 1950s, is only available in intravenous formulations and is highly toxic. With a current global death rate of over 600,000 persons per year from this fungus, this is clearly unacceptable. Thus, in a collaboration with the National Center for Advancing Therapeutics (NCAT) we set out to identify potential new drugs from a library of 4000 compounds of pharmacologically active compounds. This resulted in identification of new lead compounds that are being tested further including identification of active site targets.

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2014
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Mehta, Gautam U; Panackal, Anil A; Murayi, Roger et al. (2018) Corticosteroids for shunted previously healthy patients with non-HIV cryptococcal meningoencephalitis. J Neurol Neurosurg Psychiatry 89:219-220
Elsegeiny, Waleed; Marr, Kieren A; Williamson, Peter R (2018) Immunology of Cryptococcal Infections: Developing a Rational Approach to Patient Therapy. Front Immunol 9:651
Opintan, Japheth A; Awadzi, Benedict K; Biney, Isaac J K et al. (2017) High rates of cerebral toxoplasmosis in HIV patients presenting with meningitis in Accra, Ghana. Trans R Soc Trop Med Hyg 111:464-471
Neal, Lori M; Xing, Enze; Xu, Jintao et al. (2017) CD4+ T Cells Orchestrate Lethal Immune Pathology despite Fungal Clearance during Cryptococcus neoformans Meningoencephalitis. MBio 8:
Kwon-Chung, Kyung J; Bennett, John E; Wickes, Brian L et al. (2017) The Case for Adopting the ""Species Complex"" Nomenclature for the Etiologic Agents of Cryptococcosis. mSphere 2:
Sun, Wei; He, Shihua; Martínez-Romero, Carles et al. (2017) Synergistic drug combination effectively blocks Ebola virus infection. Antiviral Res 137:165-172
Park, Yoon-Dong; Sun, Wei; Salas, Antonio et al. (2016) Identification of Multiple Cryptococcal Fungicidal Drug Targets by Combined Gene Dosing and Drug Affinity Responsive Target Stability Screening. MBio 7:
Williamson, Peter R (2016) Role of laccase in the virulence of Talaromyces marneffei: A common link between AIDS-related fungal pathogens? Virulence 7:627-9
Panackal, Anil A; Williamson, Kim C; van de Beek, Diederik et al. (2016) Fighting the Monster: Applying the Host Damage Framework to Human Central Nervous System Infections. MBio 7:e01906-15
Hu, Guowu; McQuiston, Travis; Bernard, Amélie et al. (2016) Tor-dependent post-transcriptional regulation of autophagy: Implications for cancer therapeutics. Mol Cell Oncol 3:e1078923

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