BCAP/PI3K regulation of innate immunity to Listeria monocytogenes

BCAP/PI3K 对单核细胞增生李斯特氏菌先天免疫的调节

基本信息

批准号：
9214306
负责人：
Jessica A Hamerman
金额：
$ 43.5万
依托单位：
BENAROYA RESEARCH INST AT VIRGINIA MASON
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2020-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9214306
关键词：
1-Phosphatidylinositol 3-Kinase Adult Affect Autoimmune Diseases B-Lymphocytes Bacteria Bacterial Infections Biochemical Catalytic Domain Cell Proliferation Clinical Disease Disease Outbreaks Drug Targeting Evaluation Event FOXO1A gene Hepatocyte Human Immune response Immunocompromised Host Infection Infection Control Inflammation Inflammatory Inflammatory Response Innate Immune Response Listeria Listeria monocytogenes Listeriosis Liver Macrophage Activation Microbe Mouse Strains Mus Myeloid Cells Natural Immunity Pathogenesis Pathologic Pathway interactions Phenotype Pregnant Women Receptor Signaling Recruitment Activity Regulation Role Salmonella enterica Salmonella typhimurium Shock Signal Transduction Spleen Systemic infection Testing Tissues Toll-like receptors Wild Type Mouse adaptive immune response adaptive immunity aged experimental study foodborne gain of function immunoregulation in vivo inhibitor/antagonist insight loss of function macrophage monocyte novel pathogen public health relevance response therapeutic target

项目摘要

DESCRIPTION (provided by applicant): After pathogen recognition, macrophages initiate an inflammatory response, a critical event that orchestrates both the innate and adaptive immune responses to pathogens. Whereas inflammation is required for a productive immune response, inflammation in excess can cause pathological consequences, including tissue damage, inflammatory and autoimmune disease, or, in its most severe form, systemic shock. Therefore, appropriate control of the inflammatory response is essential for pathogen clearance and protection from excessive inflammation. B cell adapter for PI3-kinase (BCAP) is a novel negative regulator of macrophage inflammatory responses induced by Toll-like receptors through its ability to activate PI3K. BCAP also inhibits innate immune responses to Listeria monocytogenes (Lm) infection, highlighting the detrimental aspects of inhibitors of inflammation to bacterial clearance. In comparison with wild-type mice, mice lacking BCAP had increased clearance of systemic Lm infection, and a dramatic increase in inflammatory monocyte accumulation in the spleen, which we hypothesize results in the increased clearance of bacteria. BCAP also regulates splenic monocyte accumulation during infection with Salmonella enterica serovar Typhimurium. Therefore, BCAP is a key modulator of innate responses to bacterial infection. The aims of this proposal seek to better understand the mechanisms by which BCAP regulates the innate immune response to infection with Lm. In Aim 1, we will define the specific mechanisms by which BCAP inhibits TLR signaling, testing whether BCAP uses Flii and/or Lrrfip2, p110beta and Foxo1 to inhibit TLR responses. We will also test whether BCAP similarly inhibits TLR responses in human monocytes through activation of PI3K. In Aim 2, we will determine how BCAP regulates inflammatory monocyte accumulation during and Lm clearance in vivo. We will examine 1) whether BCAP-deficiency in inflammatory monocytes is required for increased clearance of Lm and increased accumulation of splenic monocytes, 2) whether BCAP regulates monocyte accumulation by affecting cell proliferation and/or survival, and 3) if increasing PI3K activity in monocytes can reverse the phenotype of BCAP-/- mice during Lm infection. We will also extend these studies to infection with Salmonella Typhimurium. Together, these experiments will give a comprehensive view of how BCAP controls monocyte responses to bacterial infections of clinical importance. Understanding the mechanisms by which BCAP regulates inflammation will define how to therapeutically target the BCAP signaling axis for the control of infection and inflammatory diseases.

描述（由申请人提供）：识别病原体后，巨噬细胞启动炎症反应，这是协调对病原体的先天性和适应性免疫反应的关键事件，包括组织损伤、炎症和自身免疫性疾病，或者最严重的形式是全身性免疫反应。因此，适当控制炎症反应对于清除病原体和防止 PI3 激酶过度炎症至关重要。 (BCAP) 是 Toll 样受体通过激活 PI3K 诱导的巨噬细胞炎症反应的新型负调节因子，BCAP 还可以抑制对单核细胞增多性李斯特菌 (Lm) 感染的先天免疫反应，这凸显了炎症抑制剂对细菌清除的不利影响。与野生型小鼠相比，缺乏 BCAP 的小鼠对全身性 Lm 感染的清除增加，并且脾脏中炎症单核细胞积聚显着增加，我们捕获了导致BCAP 还调节鼠伤寒沙门氏菌感染期间的脾单核细胞积聚，因此，BCAP 是细菌感染先天反应的关键调节剂。本提案的目的旨在更好地了解 BCAP 调节先天免疫反应的机制。在目标 1 中，我们将定义 BCAP 抑制 TLR 信号传导的具体机制，测试 BCAP 是否使用 Flii 和/或 Lrrfip2， p110beta 和 Foxo1 抑制 TLR 反应我们还将测试 BCAP 是否通过激活 PI3K 类似地抑制人类单核细胞的 TLR 反应在目标 2 中，我们将确定 BCAP 如何在体内调节炎症单核细胞积聚和 Lm 清除。 ) 炎症单核细胞中的 BCAP 缺陷是否是 Lm 清除率增加和脾单核细胞积累增加所必需的，2) BCAP 是否调节通过影响细胞增殖和/或存活来抑制单核细胞的积累，以及 3) 增加单核细胞中的 PI3K 活性是否可以逆转 Lm 感染期间 BCAP-/- 小鼠的表型。我们还将这些研究扩展到鼠伤寒沙门氏菌感染。将全面了解 BCAP 如何控制单核细胞对具有临床重要性的细菌感染的反应。了解 BCAP 调节炎症的机制将确定如何在治疗上靶向 BCAP 信号轴来控制感染和炎症性疾病。