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 affects the virulence of Cryptococcus neoformans. The specific hypothesis behind the present proposal is that a virulence associated DEAD-box protein, Vad1, identified by insertional mutagenesis, is an important regulator of laccase and virulence in C. neoformans. This is based on the following observations. First, deletion of VAD1 results in loss of virulence and accelerated clearance of C. neoformans from lung in mouse models. Second, differential display has shown that deletion of VAD1 results in altered transcription of a number of genes in addition to laccase. Finally, deletion of one of the genes showing VAD1-dependent transcription, PCK1, exhibited attenuated virulence in a mouse model in spite of retained laccase activity. In the last project period, we completed a detailed biochemical analysis of the mechanism of Vad1-dependent degradation of the MFalpha mating pheromone and the role of this regulation in mating. We also continued our studies of the role of autophagy in cryptococcal pathogenesis by detailing the role of ATG8 regulation of this important virulence-related phenotype. In addition, we identified a role for copper acquisition in cryptococcal pathogenesis and determined a role of increased copper quota in cryptococcal metabolism. Finally, we showed that the immune response was attenuated to vad1 delta mutants using a mouse clearance model. In conclusion, our studies in the most recent period have shown new methods of virulence regulation in the AIDS-related pathogen, Cryptococcus neoformans that could have applications toward novel drug and control strategies for this important pathogen.

Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2010
Total Cost
$604,665
Indirect Cost
City
State
Country
Zip Code
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

Showing the most recent 10 out of 39 publications