Role Of Innate Immunity In The Initiation And Pathogenes

先天免疫在起始和病原体中的作用

• 批准号: 6986990
• 负责人: Anthony S. Fauci
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6986990
• 关键词: CD95 molecule; HIV infections; apoptosis; biological signal transduction; cell proliferation; chemokine; chemokine receptor; enzyme linked immunosorbent assay; flow cytometry; gene induction /repression; host organism interaction; human immunodeficiency virus; human tissue; immunomagnetic separation; interferons; lectin; microarray technology; microorganism culture; microorganism immunology; natural killer cells; pathologic process; receptor expression; virus envelope; virus infection mechanism; virus load

Innate immunity is the first line of defense designed to protect the host from invading pathogens, including HIV. We have previously demonstrated that suppression of natural killer (NK) cell function can be profound and that it is related to the stage of HIV infection as well as the level of HIV plasma viremia. Our study revealed that HIV viremia impairs the ability of NK cells to secrete CC-chemokines and alters the expression of various inhibitory and chemokine receptors expressed on NK cells. Further analysis of NK-cell specific surface receptors revealed upregulation of inhibitory NK receptors and chemokine receptor CCR5. In addition, our data showed CCR5 upregulation to be induced as a result of immune activation while induction of iNKRs appeared to be a direct result of an HIV-induced effect. Analysis of NK cell interactions with R5 and X4 HIV envelopes showed profound suppression of generic NK cell function upon exposure to these envelopes. Furthermore, DNA microarray analyses of NK cells in the presence and absence of HIV envelopes delineated upregulation of several genes that were important in inducing apoptosis and suppression of cell proliferation. Similarly, exposure to HIV envelopes suppressed the expression of several genes critical for cell proliferation and generic NK cell function. Functional studies confirmed the profound suppresssive ability of HIV envelopes on generic NK cell functions such as cytotoxicity, proliferation, and secretion of cytokines and chemokines. Future studies will be focused on delineating the underlying mechanisms involved in the interaction between R5 and X4 HIV envelopes and NK cells. Further studies will address the cellular and molecular basis for this HIV envelope-induced suppressive effect on NK cells. Specific roles of NK cell receptors, particularly those belonging to the C-type lectin family will be investigated as potential igands for HIV envelopes. DNA microarray analyses of NK cells from HIV viremic patients showed upregulation of genes induced by interferon when compared with those from HIV aviremic individuals and HIV seronegative normal volunteers. Analyses of these gene clusters have lead us to identify pathways of signal transduction that are abnormally regulated in HIV viremic state. We have further demonstrated that NK cells from HIV viremic patients express relatively higher levels of fas molecule on their surface and are susceptible to fas-mediated apoptosis upon exposure to sFASL. In addition, NK cells from HIV viremic individuals have reduced surface expresssion of interleukin receptors and express significantly higher levels of intracellular Ki67, indicating a higher level of cellular activation associated with the HIV viremic state. We have further demonstrated that HIV-infected individuals have elevated levels of sfas and SFASL circulating in the serum during viremia when compared to the levels of these molecules during the aviremic state. These observations indicate a profound effect of HIV viremic state on the ability of NK cells to proliferate, undergo chemotaxis, and ultimately to survive in vivo. Future experiments will be focused on evaluating the turnover of NK cells in vivo after administration of BRDU. Such experiments will help us to understand the nature of NK cell proliferation and turnover in the HIV viremic state.

先天免疫是旨在保护宿主免受入侵病原体（包括艾滋病毒）的第一道防线。我们先前已经证明，自然杀伤（NK）细胞功能的抑制可能是深刻的，并且与HIV感染阶段以及HIV血浆病毒血症的水平有关。我们的研究表明，HIV病毒血症会损害NK细胞分泌CC化学家的能力并改变NK细胞上表达的各种抑制性和趋化因子的表达。对NK细胞特异性表面受体的进一步分析表明，抑制性NK受体和趋化因子受体CCR5上调。此外，我们的数据显示，由于免疫激活而引起的CCR5上调，而诱导INKR似乎是HIV诱导的作用的直接结果。 NK细胞与R5和X4 HIV信封的分析在暴露于这些信封后对通用NK细胞功能的深刻抑制。此外，在存在和不存在HIV信封的情况下，对NK细胞进行了DNA微阵列分析，描绘了几种对诱导细胞凋亡和抑制细胞增殖至关重要的基因上调。同样，暴露于HIV信封抑制了几种对细胞增殖和通用NK细胞功能至关重要的基因的表达。功能研究证实了HIV信封对通用NK细胞功能的深刻抑制能力，例如细胞毒性，增殖和细胞因子和趋化因子的分泌。未来的研究将集中于描述R5和X4 HIV包膜与NK细胞之间相互作用所涉及的潜在机制。进一步的研究将解决该HIV包膜诱导的NK细胞抑制作用的细胞和分子基础。 NK细胞受体的特定作用，尤其是属于C型凝集素家族的受体，将被研究为HIV信封的潜在IGAND。 与HIV Avirememic个个体和HIV血清阴道正常志愿者相比，对HIV病毒患者NK细胞的DNA微阵列分析表明，干扰素诱导的基因上调。这些基因簇的分析使我们确定了在HIV病毒性状态中受异常调控的信号转导途径。我们进一步证明，来自HIV病毒患者的NK细胞在其表面表现出相对较高的FAS分子水平，并且在暴露于SFASL时易受FAS介导的细胞凋亡。另外，来自HIV病毒个体的NK细胞减少了白介受体的表面表达，并表达明显更高水平的细胞内KI67，表明与HIV病毒性状态相关的细胞活化水平较高。我们进一步证明，与阿维病态状态期间这些分子的水平相比，在病毒血症期间，艾滋病毒感染的个体在血清中的SFA和SFASL水平升高。这些观察结果表明，HIV病毒性状态对NK细胞增殖，进行趋化性并最终在体内生存的能力产生了深远的影响。未来的实验将集中于评估BRDU给药后体内NK细胞的周转率。这样的实验将帮助我们了解NK细胞增殖的性质和HIV病毒性状态的周转。