During the previous funding period, we have continued to recruit at the NIH clinical center, a cohort of disseminated cryptococcosis in otherwise symptomatically healthy individuals. We have thus far recruited 40 patients and have begun immunological and genetic characterizations. A subset of these patients that were not responding to conventional therapy were found to exhibit an overly robust immune response with ventriculitis and cerebral edema which was found to be steroid responsive. In a cohort of candidemia patients we have identified a key genetic locus associated with poor outcome and have obtained a mouse knockout strain and are conducting backcrossing experiments to more rigorously test and validate the genetic associations found in the clinical outcomes trial. In addition, we used multiplex meta-analysis of RNA expression patterns from patients with primary immune deficiencies to prioritize genes that are altered in association with known genetic defects. These studies identifed known PID-associated genes such as MS4A1 (CD20),RSAD2 and Stat1 as well as less characterized genes such as Map4K4 that has been shown in mice to be involved in macrophage TNFalpha and IL1beta secretion. We also completed an epidemilogy study of cryptococcosis in the US during a 13 year period, in collaboration with B. Prevots, LCID/NIAID/NIH which idenfied over 30,000 hospitalizations over the study period with a hospital-associated cost of approximately USD 0.5 Billion, suggesting that, despite improvments in therapy and prevention of HIV/AIDS, that cryptococcosis remains an important fungal disease in the US with substantial human and economic cost.

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Williamson, Peter R; Jarvis, Joseph N; Panackal, Anil A et al. (2017) Cryptococcal meningitis: epidemiology, immunology, diagnosis and therapy. Nat Rev Neurol 13:13-24
Panackal, Anil A; Komori, Mika; Kosa, Peter et al. (2017) Spinal Arachnoiditis as a Complication of Cryptococcal Meningoencephalitis in Non-HIV Previously Healthy Adults. Clin Infect Dis 64:275-283
Panackal, Anil A; Rosen, Lindsey B; Uzel, Gulbu et al. (2017) Susceptibility to Cryptococcal Meningoencephalitis Associated With Idiopathic CD4+ Lymphopenia and Secondary Germline or Acquired Defects. Open Forum Infect Dis 4:ofx082
Williamson, Peter R (2017) The relentless march of cryptococcal meningitis. Lancet Infect Dis 17:790-791
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:
Montezuma-Rusca, Jairo M; Powers, John H; Follmann, Dean et al. (2016) Early Fungicidal Activity as a Candidate Surrogate Endpoint for All-Cause Mortality in Cryptococcal Meningitis: A Systematic Review of the Evidence. PLoS One 11:e0159727
Williamson, Peter R; Nash, Theodore E; Williamson, Kim C et al. (2016) CNS infections in 2015: emerging catastrophic infections and new insights into neuroimmunological host damage. Lancet Neurol 15:17-9
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
Panackal, Anil A; Marr, Kieren A; Williamson, Peter R (2016) Dexamethasone in Cryptococcal Meningitis. N Engl J Med 375:188

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