SC COBRE: ROLE OF IPC1 IN REGULATION OF PHAGOCYTOSIS OF C NEOFORMANS

SC COBRE：IPC1 在调节 C Neoformans 吞噬作用中的作用

• 批准号: 7610442
• 负责人: Maurizio Del Poeta
• 金额: $ 6.87万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7610442
• 关键词: Alveolar Macrophages; Cells; Computer Retrieval of Information on Scientific Projects Database; Condition; Cryptococcus neoformans; Cryptococcus neoformans infection; Development; Disease; Encephalitis; Funding; Genes; Goals; Grant; Host Defense; Human; Immune; Immunocompromised Host; Infection; Institution; Lead; Life; Microbe; Molecular; Mus; Organism; Outcome; Pathogenicity; Phagocytes; Phagocytosis; Process; Proteins; Regulation; Research; Research Personnel; Resources; Respiratory System; Role; Source; Testing; United States National Institutes of Health; attenuation; fungus; insight; killings; macrophage; mouse model; mutant; novel; novel therapeutics; pathogen; response

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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 Cn at the host-microbe interface. Importantly, these studies will potentially provide new therapeutic approaches to better control the development of cryptococcal infection.

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