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（由申请人提供）：肠道上皮屏障完整性的破坏是 HIV 感染期间与肠道和全身炎症相关的一个主要因素，因为它允许微生物易位（MT）穿过肠细胞屏障，解释 HIV 感染期间 MT 增加的一种理论是上皮紧密连接的破坏，进而导致肠腔细菌和细菌抗原的粘膜渗透增加到肠道固有层，然后进入体循环，导致炎症。在 cART 治疗后，即使在发生显着病毒抑制的 HIV 感染者中，细胞因子干扰素-γ (IFN) 也会增加胃肠道 (GI) 上皮屏障的通透性。 IFN- 的来源令人费解，特别是考虑到在疾病早期就已被感染。患者的肠道 CD4+ T 细胞（包括 Th1 细胞）严重耗尽，而且肠道 CD4+ T 细胞的恢复相对较慢，因此它们对 IFN 的贡献可能微乎其微。 HIV 特异性 CD8+ T 细胞在 HIV 感染期间提供 IFN 来源，而在 cART 期间它们对 HIV 抗原的反应会减弱。 IFN 的另一个主要来源是先天淋巴细胞：自然杀伤细胞 (NK) 和先天淋巴细胞 (ILC)。初步数据表明，当从病毒血症的 HIV 感染者中获得时，肠道来源的 NK/ILC（包括那些表达 NK 激活受体 NKp44 的细胞）产生 IFN 的频率较高，如下所示：与从未感染个体胃肠道获得的细胞相比，我们发现 HIV 创造了一个环境，将 NK/ILC 的功能从对维持胃肠道稳态很重要的细胞转变为导致炎症和屏障功能障碍增加的细胞。我们假设 HIV 通过以下方式直接和间接诱导炎症 NK/ILC：1) 刺激肠髓系树突状细胞 (mDC) 分泌促炎细胞因子 2)改变肠道微生物组以增加致病细菌，进而触发 mDC 分泌更高水平的促炎细胞因子 3) 诱导 CD4+ T 细胞上 NKp44 配体的表达，从而触发 ILC3（通常分泌 IL-22）开始分泌 IFN 和肿瘤坏死因子 α (TNFa) 和 4) 诱导 HIV 感染的 T 细胞上配体的表达，进而触发为了解决这些假设，我们提出以下建议： 具体目标 1：确定 HIV 和 HIV 改变的粘膜细菌 (HAMB) 诱导结肠炎症 ILC3 的机制。具体目标 2：确定 HIV 和 HAMB 导致促炎肠道 NK1/ILC1 频率增加的机制 具体目标 3：评估肠道之间的关系。 NK/ILC 细胞因子谱、NK/ILC 激活受体配体的表达、上皮屏障功能以及未经治疗和治疗的 HIV 感染期间的炎症。