Immunopathology of the Pneumocystis Life Cycle Stages

肺孢子虫生命周期阶段的免疫病理学

• 批准号: 8696764
• 负责人: Melanie T Cushion
• 金额: --
• 依托单位: CINCINNATI VA MEDICAL CENTER RESEARCH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8696764
• 关键词: 3-Dimensional; Aging; Alveolar Macrophages; Anidulafungin; Animals; Binding; Biological Assay; CD8B1 gene; Cell Wall; Chronic Disease; Chronic Obstructive Airway Disease; Clinical; Comorbidity; Complication; Cyst; Development; Ensure; Equilibrium; Gene Expression; Glucans; Goals; Growth; HIV; Human; Immune; Immune response; Immune system; In Vitro; Infection; Infectious Agent; Inflammatory Response; Leukocytes; Life; Life Cycle Stages; Lung; Malignant neoplasm of lung; Mammals; Molecular; Molecular Profiling; Mus; Mycoses; Natural History; Opportunistic Infections; Organism; Partner in relationship; Pathogenesis; Patients; Persons; Phagocytosis; Phase; Pneumocystis; Pneumocystis Infections; Pneumocystis carinii Pneumonia; Pneumonia; Population; Rattus; Registries; Reproduction spores; Research Personnel; Risk; Role; Route; Series; Severity of illness; Silver Methenamine; Staging; Staining method; Stains; System; T-Lymphocyte; Thick; Travel; Veterans; asexual; beta-1,3-D-glucan; cytokine; effective therapy; fungus; immunopathology; immunosuppressed; in vivo; infected vector rodent; inhibitor/antagonist; insight; mortality; receptor; reconstitution; response; tool; transmission process

DESCRIPTION (provided by applicant): Fungal organisms in the genus Pneumocystis, were first clinically noticed because they caused an oftentimes lethal pneumonia (PCP) in humans and other mammals with compromised immune status. Today, the niche of these fungi have expanded to include patients with underlying chronic diseases like COPD, where their presence has been suggested to be a co-morbidity factor. Limited progress has been made in understanding the life cycle, transmission, and natural history of Pneumocystis, due in large part to the absence of a continuous in vitro culture system. The strategies used by these organisms to grow and survive in the context of an intact or immune-debilitated host are largely unknown. The actual agent of infection, the transmissive form, has not been identified, nor has its mode of travel, generally thought to be via an airborne spore. The life cycle of Pneumocystis involves trophic forms (trophs), thought to be the vegetative, asexually dividing life cycle stage; as well as several other developmental stages including the cyst form, which contains 8 ascospores. The cyst is distinct from the trophs in that it contains a thick cell wall comprised mostly of B-1,3 glucan; is larger (5-8um vs 1-4um); and stains with the fungal wall stain, methenamine silver. Cyst formation is thought to result from mating of trophs, but the interplay between the asexual and sexual phases is not clear. During the tenure of the previous Merit Review, we found that the treatment of Pneumocystis infections with echinocandins suppressed the formation of B-1,3-glucan thereby dramatically shifting the mixed cyst and troph populations in immunosuppressed mice and rats to one made almost exclusively of trophic forms. Strikingly, the mortality was markedly reduced in these mice, yet large populations of trophs were present in their lungs. Moreover, echinocandin treated mice were unable to transmit the infection. In the present proposal, we will use the echinocandins as molecular tools to dissect the life cycle in a manner that has never been available to investigators before. It is our central hypothesis that the asexual and sexual cycles act in concert to maintain a balance within the mammalian lung that permits a long and sustainable infection that ensures sustained transmission without demise of the host. We posit that cysts are the agents of transmission and the process of cyst formation requires B-1,3-glucan. However, the presence of cysts via B-1,3 glucan induces a detrimental inflammatory response in the host that increases severity of disease. In the present proposal, we will identify the immune responses evoked by each different population and dissect the life cycle of Pneumocystis using the echinocandins. Towards these goals, we propose the following specific aims: (1) Dissect the Pneumocystis life cycle using the echinocandin, anidulafungin, as a molecular tool by transcriptional analyses and in vivo studies to assess transmission and identify the infectious agent of Pneumocystis infection; (2) Characterize the P. murina cyst and trophic form interactions with alveolar macrophages through a series of binding and phagocytosis assays; and (3) Investigate the role of P. murina cysts in the deleterious pulmonary hyperinflammatory response following immune reconstitution by evaluating cytokine and cellular profiles in the lungs of cyst replete and cyst depleted populations of P. murina.

描述（由申请人提供）：