The long-term goal of this project is to elucidate the molecular mechanism(s) controlling the phagocytic process of the pathogenic fungus Cryptococcus neoformans (Cn) by host alveolar macrophages (AMs). Understanding these regulatory mechanisms will reveal new therapeutic strategies for the attenuation of the disease process. Cn is an opportunistic and facultative intracellular fungal pathogen that infects humans via the respiratory tract. Dissemination of the infection leads to development of a life-threatening meningo-encephalitis, particularly in immunocompromised patients. Phagocytosis of Cn by AMs represents the first line of defense by the host, and the killing of the organism is controlled by an efficient host-cell response. However, in conditions of cellular immune deficiency, phagocytosis may become detrimental for the host because Cn can grow and disseminate within macrophages. Thus, internalization of Cn by phagocytic cells may be considered either an obstacle or an opportunity for disease development, and fungal factors that control the phagocytic process may assume a crucial role in the outcome of the infection. We identified a novel cryptococcal gene encoding for an antiphagocytic protein 1 (App1), which inhibits phagocytosis of Cn by AMs. A Cn mutant lacking App1 is less pathogenic in a mouse model with a functional host-cell response but, intriguingly, more pathogenic in mice with impaired host-cell response compared to Cn wild-type strain. These observations lead us to hypothesize that App1 modulates pathogenicity of Cn through the regulation of phagocytosis by AMs. This hypothesis will be tested by the following Specific Aims: 1) Determine the mechanisms by which App1 regulates phagocytosis, and 2) determine the role and function of Ap1 in the outcome of cryptococcosis. These studies will produce new insights into the mechanisms of pathogenicity of C. neoformans at the host-microbe interface. Importantly, these studies will potentially provide new therapeutic approaches to better control the development of cryptococcal infection. Cryptococcus neoformans is an environmental microorganism that causes the most common fungal meningo-encephalitis worldwide. The pathologenesis of this fungal pathogen is not well understood. This proposal focuses on a better understanding of the pathogenic process, providing new insights into the development of better therapeutic strategies against this life-threatening fungal brain infection

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
7R01AI071142-06
Application #
8518822
Study Section
Special Emphasis Panel (ZRG1-IDM-F (02))
Program Officer
Duncan, Rory A
Project Start
2007-12-15
Project End
2014-11-30
Budget Start
2012-06-01
Budget End
2014-11-30
Support Year
6
Fiscal Year
2012
Total Cost
$160,925
Indirect Cost
$58,425
Name
State University New York Stony Brook
Department
Genetics
Type
Schools of Medicine
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
Rella, Antonella; Farnoud, Amir M; Del Poeta, Maurizio (2016) Plasma membrane lipids and their role in fungal virulence. Prog Lipid Res 61:63-72
Singh, Ashutosh; Del Poeta, Maurizio (2016) Sphingolipidomics: An Important Mechanistic Tool for Studying Fungal Pathogens. Front Microbiol 7:501
Farnoud, Amir M; Toledo, Alvaro M; Konopka, James B et al. (2015) Raft-like membrane domains in pathogenic microorganisms. Curr Top Membr 75:233-68
Singh, Arpita; Rella, Antonella; Schwacke, John et al. (2015) Transmembrane transporter expression regulated by the glucosylceramide pathway in Cryptococcus neoformans. BMC Res Notes 8:681
Mor, Visesato; Rella, Antonella; Farnoud, Amir M et al. (2015) Identification of a New Class of Antifungals Targeting the Synthesis of Fungal Sphingolipids. MBio 6:e00647
Bryan, Arielle M; Del Poeta, Maurizio; Luberto, Chiara (2015) Sphingolipids as Regulators of the Phagocytic Response to Fungal Infections. Mediators Inflamm 2015:640540
Farnoud, Amir M; Bryan, Arielle M; Kechichian, Talar et al. (2015) The Granuloma Response Controlling Cryptococcosis in Mice Depends on the Sphingosine Kinase 1-Sphingosine 1-Phosphate Pathway. Infect Immun 83:2705-13
Rella, Antonella; Mor, Visesato; Farnoud, Amir M et al. (2015) Role of Sterylglucosidase 1 (Sgl1) on the pathogenicity of Cryptococcus neoformans: potential applications for vaccine development. Front Microbiol 6:836
Bryan, Arielle M; Farnoud, Amir M; Mor, Visesato et al. (2014) Macrophage cholesterol depletion and its effect on the phagocytosis of Cryptococcus neoformans. J Vis Exp :
Farnoud, Amir M; Mor, Visesato; Singh, Ashutosh et al. (2014) Inositol phosphosphingolipid phospholipase C1 regulates plasma membrane ATPase (Pma1) stability in Cryptococcus neoformans. FEBS Lett 588:3932-8

Showing the most recent 10 out of 31 publications