DAP12 and the host response to cryptococcosis

DAP12 和宿主对隐球菌病的反应

• 批准号: 10449347
• 负责人: Lena J Heung
• 金额: $ 57.18万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-12 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10449347
• 关键词: AIDS/HIV problem; Antifungal Therapy; Antigen-Presenting Cells; Autoimmunity; Bacteria; Binding; Bone Marrow; Brain; CD8-Positive T-Lymphocytes; Cell Surface Receptors; Cells; Complex; Cryptococcosis; Cryptococcus; Cryptococcus neoformans; Cryptococcus neoformans infection; Data; Defect; Dendritic Cells; Development; Disease Progression; Dissection; Genetic; Goals; ITAM; Immune; Immune response; Immune system; Immunity; Immunocompromised Host; Individual; Industrial fungicide; Infection; Inflammatory; Inflammatory Response; Inhalation; Intervention; Life; Lung; Malignant Neoplasms; Mediating; Meningoencephalitis; Modeling; Molecular; Mus; Mycoses; Myelogenous; Myeloid Cells; Natural Killer Cells; Organ Transplantation; Outcome; Patients; Phagocytosis; Play; Populations at Risk; Production; Proteins; Receptor Signaling; Regimen; Regulation; Resolution; Role; Signal Pathway; Signal Transduction; Solid; T cell response; T-Cell Proliferation; TNF gene; TREM2 gene; Toll-like receptors; adaptive immune response; cytokine; cytotoxic; fungus; immunoregulation; improved; in vitro Model; in vivo; macrophage; monocyte; mortality; mouse model; novel; novel strategies; pathogenic fungus; prevent; receptor; recruit; response; therapy development; tool; uptake

Project Summary Cryptococcus neoformans is an opportunistic fungal pathogen that is inhaled into the lungs and can disseminate to the brain, causing a highly fatal meningoencephalitis in immunocompromised patients, particularly those with HIV/AIDS, solid organ transplantation, and cancer. Even with contemporary combination antifungal therapy, the mortality rate for cryptococcosis approximates 25%, and the at-risk population is expanding with the development of new immunosuppressive regimens for autoimmunity and cancer. Our ability to develop new treatments for cryptococcosis remains limited because we do not yet fully understand how the fungus evades host immunity. We recently discovered that C. neoformans is able to suppress the response of inflammatory monocytes, innate immune cells that give rise to macrophages and dendritic cells and typically aid in fungal recognition and clearance by the host. C. neoformans directs inflammatory monocytes to differentiate into alternatively activated (M2) macrophages that are permissive for fungal proliferation and dissemination, leading to increased mortality from the infection. We have identified a signaling adapter DNAX- activating protein of 12 kDa (DAP12) that may play a crucial role in suppressing the inflammatory monocyte response to C. neoformans. The deletion of DAP12 improves fungal clearance and survival in a murine model of cryptococcosis, and DAP12-deficient monocyte-derived macrophages have better uptake and killing of the fungus. Additionally, the lungs of Dap12-/- mice have increased numbers of CD8+ T cells, cytotoxic adaptive immune cells that can be recruited and activated by macrophages and are important for the clearance of C. neoformans. Thus, DAP12 may be an important target for reversing the suppressive effects of C. neoformans on the fungicidal activity of inflammatory monocytes and their ability to prime CD8+ T cells. Our preliminary data indicate that this repressive DAP12 activity may be regulated by the binding of C. neoformans to the cell surface receptor triggering receptor expressed on myeloid cells 2 (TREM2) on monocyte-derived macrophages. The goal of this proposal is to further define this novel DAP12 signaling pathway. We hypothesize that C. neoformans induces formation of a TREM2-DAP12 signaling complex that coordinates effector molecules to inhibit the anti-cryptococcal defenses of inflammatory monocytes and CD8+ T cells, thereby subverting the host response to infection. The specific aims are to 1) determine the mechanism by which DAP12 signaling is initiated by C. neoformans, 2) define the signaling cascade that mediates the suppressive effects of DAP12 during infection, and 3) ascertain the role of inflammatory monocyte-intrinsic DAP12 in the regulation of CD8+ T cell responses to C. neoformans. Defining these mechanisms will deepen our understanding of host immunity to opportunistic fungi and inform new opportunities for immunomodulatory interventions against C. neoformans in vulnerable hosts.

项目总结