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：
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
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/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

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.

项目概要新型隐球菌是一种机会性真菌病原体，被吸入肺部并可传播到大脑，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毒/艾滋病、实体器官移植和癌症的人。即使是现代组合抗真菌治疗后，隐球菌病的死亡率约为25%，高危人群为随着针对自身免疫和癌症的新免疫抑制疗法的开发而扩大。我们的能力开发隐球菌病的新疗法仍然有限，因为我们尚未完全了解隐球菌病如何真菌逃避宿主免疫。我们最近发现 C. neoformans 能够抑制炎症单核细胞、产生巨噬细胞和树突状细胞的先天免疫细胞，通常帮助宿主识别和清除真菌。新型隐球菌引导炎性单核细胞分化为选择性激活（M2）巨噬细胞，允许真菌增殖和传播，导致感染死亡率增加。我们已经鉴定出信号转导接头 DNAX- 12 kDa 的激活蛋白 (DAP12)，可能在抑制炎症单核细胞中发挥关键作用对新型隐球菌的反应。 DAP12 的缺失提高了小鼠模型中的真菌清除率和存活率隐球菌病，DAP12 缺陷型单核细胞来源的巨噬细胞具有更好的摄取和杀灭作用菌。此外，Dap12-/- 小鼠的肺部 CD8+ T 细胞数量增加，细胞毒性适应性可以被巨噬细胞招募和激活的免疫细胞，对于清除艰难梭菌很重要。新型隐球菌。因此，DAP12可能是逆转新型隐球菌抑制作用的重要靶点炎症单核细胞的杀菌活性及其启动 CD8+ T 细胞的能力。我们的初步数据表明，这种抑制性 DAP12 活性可能是通过新型隐球菌与细胞的结合来调节的表面受体触发单核细胞衍生的骨髓细胞 2 (TREM2) 上表达的受体巨噬细胞。该提案的目标是进一步定义这种新颖的 DAP12 信号通路。我们假设新型隐球菌诱导 TREM2-DAP12 信号复合物的形成，该复合物协调抑制炎症单核细胞和 CD8+ 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) 确定机制其中 DAP12 信号传导是由新型隐球菌发起的，2) 定义了介导 DAP12 在感染过程中的抑制作用，以及 3) 确定炎症单核细胞固有的作用 DAP12 调节 CD8+ T 细胞对新型隐球菌的反应。定义这些机制将加深我们对宿主对机会性真菌免疫的理解，并为免疫调节提供了新的机会针对脆弱宿主的新型隐球菌的干预措施。