Switch from homeostatic to inflammatory cytokines by NK/ILC in HIV-infected gut

HIV 感染肠道中 NK/ILC 从稳态细胞因子转变为炎性细胞因子

• 批准号: 9074923
• 负责人: Edward Barker
• 金额: $ 11.58万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-15 至 2015-08-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9074923
• 关键词: Address; Anti-Bacterial Agents; Anti-Retroviral Agents; Automobile Driving; Bacteria; Bacterial Antigens; Blood; Blood Circulation; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Communication; Cells; Chronic; Colon; Comorbidity; Data; Defect; Dendritic Cells; Disease; Enteral; Environment; Epithelial; Epithelial Cell Proliferation; Epithelial Cells; Exposure to; Family; Frequencies; Functional disorder; Gastrointestinal tract structure; Goals; Gut associated lymphoid tissue; HIV; HIV Antigens; HIV Infections; HIV-1; Health; Homeostasis; Host Defense; Individual; Infection; Inflammation; Inflammatory; Interferon Type II; Interleukin-12; Interleukin-17; Intestines; Lamina Propria; Ligands; Lymphocyte; Lymphoid Cell; Maintenance; Molecular Profiling; Morbidity - disease rate; Mucins; Mucositis; Mucous body substance; Myelogenous; NK Cell Activation; Natural Killer Cells; Necrosis; Neutrophil Infiltration; Patients; Penetration; Peptides; Permeability; Phenotype; Play; Process; Production; Proteins; Receptor Activation; Recovery; Research; Research Personnel; Role; SIV; Seminal; Source; Staging; T-Cell Activation; T-Lymphocyte; Th1 Cells; Tight Junctions; Tumor Necrosis Factor-alpha; Viral; Virus; antimicrobial; base; cytokine; effective therapy; immune activation; interleukin-22; microbial; microbiome; mortality; natural killer cell protein 44-kDa; protective effect; receptor; response; theories; tumor

 DESCRIPTION (provided by applicant): Disruption of gut epithelial barrier integrity is a major factor associated with gut and systemic inflammation during HIV infection by allowing microbial translocation (MT) across the intestinal cell barrier. One theory to explain increased MT during HIV infection is the disruption of epithelial tight junctions, which, in turn, allows increased mucosal penetration by luminal bacteria and bacterial antigens into the lamina propria of the gut and then into the systemic circulation resulting in inflammation. MT remains after cART, even in HIV-infected individuals in which significant virus suppression occurs. The cytokine interferon-gamma (IFN) increases gastrointestinal (GI) tract epithelial barrier permeability. The source of IFN- is puzzling especially given that early in the disease, infected patients have severely depleted intestinal CD4+ T-cells, including Th1 cells. Moreover, intestinal CD4+ T-cell recovery is relatively slow, so their contributions to IFN may be minimal at best. Although HIV-specific CD8+ T-cells provide a source of IFN during HIV infection, their response to HIV antigen is dampened during cART. Another major source of IFN is innate lymphocytes: natural killer cells (NK) and innate lymphoid cells (ILCs). Our preliminary data indicate that that there are higher frequencies of gut-derived NK/ILCs (including those that express the NK activation receptor, NKp44) that produce IFN when they were obtained from viremic HIV-infected individuals as compared to cells obtained from the GI tract of uninfected individuals. We hypothesize that HIV creates an environment that alters the function of NK/ILCs from cells that are important in maintaining homeostasis in the GI tract to cells that contribute to increased inflammation and barrier dysfunction in the gut of infected patients. We postulate that HIV both directly and indirectly induces inflammatory NK/ILC by 1) stimulating intestinal myeloid dendritic cells (mDC) to secrete pro- inflammatory cytokines 2) modifying the gut microbiome to increase pathobiont bacteria, which in turn trigger mDCs to secrete higher levels of pro-inflammatory cytokines 3) inducing the expression of ligands to NKp44 on CD4+ T-cells which trigger ILC3s (which normally secrete IL-22) to begin secreting IFN and tumor necrosis factor alpha (TNFa) and 4) inducing the expression of ligands on HIV-infected T-cells, which in turn, trigger pro-inflammatory NK/ILC1s to secrete IFN/TNFa. To address these hypotheses, we propose the following: Specific Aim 1: To determine the mechanism in which HIV and HIV-altered mucosal bacteria (HAMB) contribute to the induction of colonic inflammatory ILC3s. Specific Aim 2: To determine the mechanism in which HIV and HAMB contribute to increased frequencies of pro-inflammatory gut NK1/ILC1s. Specific Aim 3: To evaluate the relationship between gut NK/ ILC cytokine profiles, expression of NK/ILC activating receptor ligands, epithelial barrier function, and inflammation during untreated and treated HIV infection.

 描述（由适用提供）：肠道上皮屏障完整性的破坏是与肠道感染期间肠道和全身感染相关的主要因素，该因素通过允许在肠道屏障中微生物易位（MT）。一种解释在HIV感染期间MT增加的理论是上皮紧密连接的破坏，这又使腔细菌和细菌抗原及时在肠道上静止的层次和MT持续的层次，即使在艾滋病毒感染的个体中，也可以增加粘膜渗透，而在hiv感染了大量病毒抑制。细胞因子干扰素 - γ（IFN）增加了胃肠道（GI）上皮屏障的渗透性。 IFN-的来源令人困惑，特别是考虑到在疾病的早期，感染的患者严重耗尽了包括Th1细胞在内的肠道CD4+ T细胞。此外，肠CD4+ T细胞恢复相对较慢，因此它们对IFN的贡献最多可能是最小的。尽管HIV特异性的CD8+ T细胞在HIV感染过程中提供了IFN的来源，但在CART期间，它们对HIV抗原的反应受到抑制。 IFN的另一个主要来源是先天淋巴细胞：天然杀伤细胞（NK）和先天淋巴样细胞（ILC）。我们的初步数据表明，肠道衍生的NK/ILC（包括表达NK激活受体的那些NKP44）在从病毒HIV感染的个体中获得IFN时，与从未感染个体的GI Tract获得的细胞相比，它们会产生IFN。我们假设HIV创造了一个环境，从而改变了细胞中NK/ILC的功能，这些环境对于维持胃肠道的稳态至关重要，这些环境可导致细胞中的细胞中的稳态，从而有助于增加感染和受感染患者肠道的障碍功能障碍。我们假设HIV直接和间接地通过1）刺激肠髓细胞树突状细胞（MDC）刺激秘密促炎性细胞因子2）修改肠道微生物组以增加病原体细菌，从而增加了病原体，从而使MDC触发了较高的MDC，以触发MDC的含量3）。触发ILC3（通常是秘密IL-22）的CD4+ T细胞上的NKP44开始分泌IFN和肿瘤坏死因子Alpha（TNFA）和4）诱导了在感染HIV感染的T-Cell上的配体的表达，而T-Cell又触发了促炎的NK/I ifa/ifa nos/ifa in n n k in n k in n n k in n of norn ifa。为了解决这些假设，我们提出以下提议：具体目的1：确定艾滋病毒和艾滋病毒改变的粘膜细菌（汉堡）有助于诱导结肠炎性ILC3的机制。具体目的2：确定艾滋病毒和汉堡导致促炎肠NK1/ILC1的频率增加的机制。特定目的3：评估肠NK/ ILC细胞因子谱，NK/ ILC激活受体配体的表达，上皮屏障功能以及在未治疗和治疗的HIV感染期间注射之间的关系。