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 #
5R01AI071142-05
Application #
8197121
Study Section
Special Emphasis Panel (ZRG1-IDM-F (02))
Program Officer
Duncan, Rory A
Project Start
2007-12-15
Project End
2012-05-31
Budget Start
2011-12-01
Budget End
2012-05-31
Support Year
5
Fiscal Year
2012
Total Cost
$192,089
Indirect Cost
$60,761
Name
Medical University of South Carolina
Department
Biochemistry
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
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
Bryan, Arielle M; Del Poeta, Maurizio; Luberto, Chiara (2015) Sphingolipids as Regulators of the Phagocytic Response to Fungal Infections. Mediators Inflamm 2015:640540
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
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
Del Poeta, Maurizio; Nimrichter, Leonardo; Rodrigues, Marcio L et al. (2014) Synthesis and biological properties of fungal glucosylceramide. PLoS Pathog 10:e1003832
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
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 :

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