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

• 批准号: 9124703
• 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
• 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/9124703
• 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; Health; Hepatocyte; Human; Immune response; Immunocompromised Host; Infection; Infection Control; Inflammation; Inflammatory; Inflammatory Response; Listeria; Listeria monocytogenes; Listeriosis; Liver; Macrophage Activation; Microbe; Mouse Strains; Mus; Myeloid Cells; Natural Immunity; Pathogenesis; 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 immunity; aged; foodborne; gain of function; in vivo; inhibitor/antagonist; insight; loss of function; macrophage; monocyte; novel; pathogen; research study; response

 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，这是一个协调对病原体的先天性和适应性免疫反应的关键事件。虽然炎症是产生免疫反应所必需的，但过度的炎症可导致病理后果，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休克。因此，适当控制炎症反应对于病原体清除和防止过度炎症至关重要。B cell adapter for PI 3-kinase（BCAP）是一种新型的负性调节因子，可通过激活PI 3 K来调节Toll样受体诱导的巨噬细胞炎症反应。BCAP还抑制对单核细胞增生李斯特菌（Lm）感染的先天免疫反应，突出了炎症抑制剂对细菌清除的不利方面。与野生型小鼠相比，缺乏BCAP的小鼠对全身性Lm感染的清除率增加，脾脏中炎性单核细胞积聚显著增加，我们假设这导致细菌清除率增加。BCAP还调节鼠伤寒沙门氏菌感染期间脾单核细胞的积聚。因此，BCAP是对细菌感染的先天性应答的关键调节剂。该提案的目的是寻求更好地了解BCAP调节Lm感染的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Lrrfip 2、p110 β和Foxo 1来抑制TLR反应。我们还将测试BCAP是否通过激活PI 3 K类似地抑制人单核细胞中的TLR应答。在目标2中，我们将确定BCAP如何调节体内炎症单核细胞积聚和Lm清除。我们将检查1）炎症单核细胞中的BCAP缺陷是否是Lm清除增加和脾单核细胞蓄积增加所必需的，2）BCAP是否通过影响细胞增殖和/或存活来调节单核细胞蓄积，3）单核细胞中PI 3 K活性增加是否可以逆转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。总之，这些实验将全面了解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治疗靶向BCAP信号传导轴以控制感染和炎性疾病。