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.

Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2012
Total Cost
$310,706
Indirect Cost
City
State
Country
Zip Code
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
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
Jitmuang, Anupop; Panackal, Anil A; Williamson, Peter R et al. (2016) Performance of the Cryptococcal Antigen Lateral Flow Assay in Non-HIV-Related Cryptococcosis. J Clin Microbiol 54:460-3
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Huang, Yuefeng; Guo, Liying; Qiu, Jin et al. (2015) IL-25-responsive, lineage-negative KLRG1(hi) cells are multipotential 'inflammatory' type 2 innate lymphoid cells. Nat Immunol 16:161-9
Zhang, Nannan; Park, Yoon-Dong; Williamson, Peter R (2015) New technology and resources for cryptococcal research. Fungal Genet Biol 78:99-107
Hu, Guowu; McQuiston, Travis; Bernard, Amélie et al. (2015) TOR-dependent post-transcriptional regulation of autophagy. Autophagy 11:2390-2

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