DAP12 and the host response to cryptococcosis

DAP12 和宿主对隐球菌病的反应

基本信息

批准号：
10275306
负责人：
Lena J Heung
金额：
$ 56.93万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/10275306
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

项目摘要

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.

项目摘要加密型新外形是一种机会性真菌病原体，被吸入肺部，可以传播到大脑，导致免疫功能低下的患者高度致命的脑膜脑炎，特别是患有艾滋病毒/艾滋病的人，固体器官移植和癌症。即使有当代组合抗真菌疗法，隐球菌病的死亡率近似于25％，高危人群为随着新的自身免疫性和癌症的新免疫抑制方案的发展而扩展。我们的能力为了开发新的加密球病治疗方法仍然有限，因为我们尚未完全了解真菌逃避宿主的免疫力。我们最近发现，新梭菌能够抑制炎性单核细胞，固有的免疫细胞，产生巨噬细胞和树突状细胞，通常协助主机的真菌识别和清除。 C. Neoformans将炎症单核细胞引导到分化为允许真菌增殖的替代激活（M2）巨噬细胞传播，导致感染的死亡率增加。我们已经确定了一个信号转移dnax- 激活12 kDa（DAP12）的蛋白质在抑制炎症单核细胞中起着至关重要的作用对新生梭菌的反应。 DAP12的删除可改善鼠模型中的真菌清除和生存隐球菌病和DAP12缺陷的单核细胞衍生的巨噬细胞具有更好的吸收和杀戮菌。另外，DAP12 - / - 小鼠的肺CD8+ T细胞数量增加，细胞毒性自适应可以通过巨噬细胞募集和激活的免疫细胞，对于清除C。 Neoformans。因此，DAP12可能是逆转新甲状腺癌抑制作用的重要目标关于炎症单核细胞的杀真菌活性及其促进CD8+ T细胞的能力。我们的初步数据表明，这种抑制性DAP12活性可能受到新生梭菌与细胞的结合来调节表面受体触发受体在单核细胞衍生的髓样细胞2（trem2）上表达的受体巨噬细胞。该提案的目的是进一步定义这种新颖的DAP12信号通路。我们假设Neoformans诱导了坐标的Trem2-DAP12信号传导复合物的形成效应子分子抑制炎症单核细胞和CD8+ T细胞的抗晶状体防御，从而颠覆了宿主对感染的反应。具体目的是1）确定机制哪些DAP12信号是由C. Neoformans启动的，2）定义介导的信号级联 DAP12在感染过程中的抑制作用，以及3）确定炎症单核细胞内神经的作用 DAP12在调节CD8+ T细胞对Neoformans的反应中。定义这些机制将加深我们对宿主对机会性真菌的免疫力的理解，并为免疫调节提供新的机会在脆弱的宿主中针对新梭菌的干预措施。