DAP12 and the host response to cryptococcosis

DAP12 和宿主对隐球菌病的反应

• 批准号: 10645193
• 负责人: Lena J Heung
• 金额: $ 55.8万
• 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/10645193
• 关键词: 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; HIV/AIDS; ITAM; Immune; Immune response; Immune system; Immunity; Immunocompromised Host; Individual; Infection; Inflammatory; Inflammatory Response; Inhalation; Intervention; Life; Lung; Macrophage; Malignant Neoplasms; Mediating; Meningoencephalitis; Modeling; Molecular; Mus; Mycoses; Myelogenous; Myeloid Cells; Natural Killer Cells; Organ Transplantation; Outcome; Patients; Phagocytosis; Play; Populations at Risk; Production; Proliferating; Proteins; Receptor Signaling; Regimen; Regulation; Repression; 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 CD8 T cells; fungicide; fungus; immunoregulation; improved; in vitro Model; in vivo; monocyte; mortality; mouse model; novel; novel strategies; pathogenic fungus; permissiveness; 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.

项目摘要 新型隐球菌是一种机会性真菌病原体，被吸入肺部， 扩散到大脑，在免疫功能低下的患者中引起高度致命的脑膜脑炎， 特别是那些患有艾滋病、实体器官移植和癌症的人。即使是当代的组合 在抗真菌治疗中，隐球菌病的死亡率约为25%， 随着针对自身免疫和癌症的新免疫抑制方案的发展而扩大。我们的能力 开发新的治疗隐球菌病的方法仍然有限，因为我们还没有完全了解 真菌逃避宿主免疫我们最近发现C.新生儿能够抑制 炎性单核细胞、产生巨噬细胞和树突细胞的先天免疫细胞，并且通常 有助于宿主识别和清除真菌。C.新生儿将炎性单核细胞 分化成允许真菌增殖的交替活化（M2）巨噬细胞， 传播，导致感染死亡率增加。我们发现了一种信号适配器DNA- 12 kDa活化蛋白（DAP 12）可能在抑制炎症单核细胞中起关键作用 回应C。新人类DAP 12的缺失改善了小鼠模型中的真菌清除和存活 和DAP 12缺陷型单核细胞衍生的巨噬细胞有更好的吸收和杀死隐球菌病， 真菌此外，Dap 12-/-小鼠的肺具有增加的CD 8 + T细胞数量，细胞毒性适应性T细胞增加。 可被巨噬细胞募集和激活的免疫细胞，对清除C. 新人类因此，DAP 12可能是逆转C.新生 对炎性单核细胞的杀真菌活性及其引发CD 8 + T细胞的能力的影响。我们的初步 数据表明这种抑制性DAP 12活性可能受C.新生儿到细胞 髓样细胞表面受体触发受体2（TREM 2） 巨噬细胞该提案的目标是进一步定义这种新的DAP 12信号通路。我们 假设C.新型变形杆菌诱导TREM 2-DAP 12信号传导复合物的形成， 抑制炎性单核细胞和CD 8 + T细胞的抗隐球菌防御的效应分子， 从而破坏宿主对感染的反应。具体目标是：1）通过以下方式确定机制： 该DAP 12信令由C发起。2）定义了介导新生儿的信号级联反应， DAP 12在感染过程中的抑制作用，以及3）确定炎性单核细胞-内源性 DAP 12在调节CD 8 + T细胞对C.新人类明确这些机制将深化 我们对宿主对机会性真菌免疫的理解，为免疫调节提供了新的机会。 干预C。脆弱宿主体内的新型生物。