The environmental fungal pathogens Coccidioides and Histoplasma have been proposed as agents of warfare because of their easy availability, stability of spores, and infection by aerosolization (Casadevall and Pirofski, 2006);thus more knowledge about the pathogenesis of these closely related organisms is critical to biodefense. Each of these organisms converts to a parasitic form in mammalian hosts after inhalation of infectious spores from the soil.
We aim to understand pathogenesis of these fungi by identifying fungal genes that promote disease and manipulate the host. To do so, we propose a collaboration between two biologists who study human pathogenic fungi, one experienced in fungal evolutionary biology (John Taylor, UC Berkeley) and one experienced in fungal molecular and developmental molecular biology (Anita Sil, UCSF). Use of a comparative genomics approach to analyze Coccidioides and Histoplasma is likely to be fruitful because of their close evolutionary relationship and the similarities of their lifestyles in the soil and the host. We will take advantage of information inherent in the genomes of these pathogens and related fungi to generate a set of genes most likely to influence disease. This comparative approach will reveal genes that have undergone strong positive selection in these fungal pathogens. Additionally, we will identify conserved genes in Coccidioides and Histoplasma that are implicated in the conversion to the parasitic form of each organism by virtue of their role in Histoplasma. These studies will allow us to prioritize a testable number of candidate virulence genes that will be assessed for their role in pathogenicity in the mouse models of Coccidioides and Histoplasma infection. In addition, these studies will identify organism-specific targets for diagnosis, therapy and vaccination, and thus are designed to interface closely with Coccidioides projects proposed by Marc Orbach and John Galgiani.
Coccidioides and Histoplasma are primary pathogens that infect several hundred thousand individuals per year in the U.S. alone. Each is a significant source of morbidity and mortality in immunocompromised patients. Since very little is understood about how either fungus causes disease, the identification of fungal factors that influence pathogenesis will significantly advance the field and provide fodder for the development of new diagnostics and therapeutics.
|Torres, Rodrigo; Lan, Benson; Latif, Yama et al. (2014) Structural snapshots along the reaction pathway of Yersinia pestis RipA, a putative butyryl-CoA transferase. Acta Crystallogr D Biol Crystallogr 70:1074-85|
|Houghton, Raymond L; Reed, Dana E; Hubbard, Mark A et al. (2014) Development of a prototype lateral flow immunoassay (LFI) for the rapid diagnosis of melioidosis. PLoS Negl Trop Dis 8:e2727|
|Strotmeier, Jasmin; Mahrhold, Stefan; Krez, Nadja et al. (2014) Identification of the synaptic vesicle glycoprotein 2 receptor binding site in botulinum neurotoxin A. FEBS Lett 588:1087-93|
|Koellhoffer, Jayne F; Dai, Zhou; Malashkevich, Vladimir N et al. (2014) Structural characterization of the glycoprotein GP2 core domain from the CAS virus, a novel arenavirus-like species. J Mol Biol 426:1452-68|
|Bennett, Shannon N; Gu, Se Hun; Kang, Hae Ji et al. (2014) Reconstructing the evolutionary origins and phylogeography of hantaviruses. Trends Microbiol 22:473-82|
|Burtnick, Mary N; Brett, Paul J; DeShazer, David (2014) Proteomic analysis of the Burkholderia pseudomallei type II secretome reveals hydrolytic enzymes, novel proteins, and the deubiquitinase TssM. Infect Immun 82:3214-26|
|Koskiniemi, Sanna; Garza-Sánchez, Fernando; Sandegren, Linus et al. (2014) Selection of orphan Rhs toxin expression in evolved Salmonella enterica serovar Typhimurium. PLoS Genet 10:e1004255|
|Sabouri, Amir H; Marcondes, Maria Cecilia Garibaldi; Flynn, Claudia et al. (2014) TLR signaling controls lethal encephalitis in WNV-infected brain. Brain Res 1574:84-95|
|Vigant, Frederic; Hollmann, Axel; Lee, Jihye et al. (2014) The rigid amphipathic fusion inhibitor dUY11 acts through photosensitization of viruses. J Virol 88:1849-53|
|Relman, David A (2014) "Inconvenient truths" in the pursuit of scientific knowledge and public health. J Infect Dis 209:170-2|
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