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: 9127087
• 负责人: Edward Barker
• 金额: $ 62.29万
• 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: 2015-08-15 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9127087
• 关键词: Address; Anti-Bacterial Agents; Bacteria; Blood Circulation; CD4 Positive T Lymphocytes; Cells; Chronic; Clinical; Data; Dendritic Cells; Enteral; Environment; Epithelial; Frequencies; Functional disorder; Gastrointestinal tract structure; Goals; Gut associated lymphoid tissue; HIV; HIV Infections; HIV-1; Health; Homeostasis; Individual; Infection; Inflammation; Inflammatory; Interferon Type II; Interferons; Interleukin-18; Interleukins; Intestines; Lamina Propria; Ligands; Lymphoid Cell; Molecular Profiling; Mucins; Mucositis; Myelogenous; Natural Killer Cells; Pathogenesis; Patients; Penetration; Peptides; Play; Process; Production; Receptor Activation; SIV; Seminal; Staging; T-Lymphocyte; TNF gene; Time; cytokine; cytotoxic; gut microbiome; immune activation; interleukin-22; microbial; natural killer cell protein 44-kDa; receptor; response

 DESCRIPTION (provided by applicant): Loss of TH22 during HIV infection may contribute to decreased IL-22 presence in the gut; however, a subpopulation of innate lymphoid cells (ILCs), mainly NKp44 activation receptor expressing ILC3, is capable of maintaining IL-22 levels even when T-cells are depleted in the gastrointestinal (GI) tract. Our preliminary data indicate that that there are higher frequencies of gut-derived Natural Killer cells (NK)/ILCs (including those that express NKp44) that produce interferon-gamma (IFN-j) 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 t 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-j and TNF-a and 4) inducing the expression of ligands on HIV-infected T-cells, which in turn, trigger pro-inflammatory NK/ILC1s to secrete IFN-j/TNF-a. To address these hypotheses, we propose the following: Specific Aim 1: To evaluate the relationship between gut NK/ ILC cytokine profiles, expression of NK/ILC activating receptor ligands, and epithelial barrier function in untreated HIV infection and to determine whether associations exist between gut NK/ILC cell inflammatory cytokine production and clinical correlates of HIV pathogenesis in HIV-infected subjects on suppressive cART. Specific Aim 2: To determine the mechanism in which HIV and HIV-altered mucosal bacteria (HAMB) contribute to the induction of colonic inflammatory ILC3s Aim 3: To determine the mechanism in which HIV and HIV-altered mucosal bacteria (HAMB) contribute to increased frequencies of pro-inflammatory NK1/ILC1s.

 描述（由申请人提供）：HIV感染期间TH 22的缺失可能导致肠道中IL-22的存在减少;然而，先天淋巴细胞（ILC）亚群（主要是表达ILC 3的NKp 44活化受体）即使在胃肠（GI）道中T细胞耗尽时也能够维持IL-22水平。我们的初步数据表明，与从未感染个体的胃肠道获得的细胞相比，从病毒血症HIV感染个体获得的肠源性自然杀伤细胞（NK）/ILC（包括表达NKp 44的细胞）产生干扰素-γ（IFN-j）的频率更高。我们假设HIV创造了一个环境，改变了NK/ILC的功能，从维持胃肠道内稳态的重要细胞到感染患者肠道炎症增加和屏障功能障碍的细胞。我们假设HIV通过以下方式直接和间接诱导炎性NK/ILC：1）刺激肠髓样树突状细胞（mDC）分泌促炎细胞因子; 2）修饰肠道微生物组以增加致病菌，这反过来触发mDC分泌更高水平的促炎细胞因子3）诱导CD 4 + T细胞上NKp 44配体的表达，从而触发ILC 3（其通常分泌IL-22）开始分泌IFN-γ和TNF-α，和4）诱导HIV感染的T细胞上的配体表达，这又触发促炎性NK/ILC 1分泌IFN-γ/TNF-α。为了解决这些假设，我们提出了以下几点：具体目标1：评价肠道NK/ ILC细胞因子谱、NK/ILC活化受体配体表达和未经治疗的HIV感染中上皮屏障功能之间的关系，并确定肠道NK/ILC细胞炎性细胞因子产生与接受抑制性cART的HIV感染受试者中HIV发病机制的临床相关性之间是否存在关联。具体目标二：确定HIV和HIV改变的粘膜细菌（HAMB）有助于诱导结肠炎性ILC 3的机制目的3：确定HIV和HIV改变的粘膜细菌（HAMB）有助于增加促炎性NK 1/ILC 1频率的机制。