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How HIV-related proteins increase the susceptibility to lung injury despite anti-retroviral therapy

尽管进行了抗逆转录病毒治疗，HIV相关蛋白如何增加肺损伤的易感性

基本信息

批准号：
10442363
负责人：
David Marshall Guidot
金额：
$ 39万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-15 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10442363
关键词：
Acute Alveolar Alveolar Macrophages Animal Model Antioxidants Cause of Death Cell Culture System Cells Chronic Chronic lung disease Clinical Trials Coculture Techniques Complement Data Development Disease Progression Environment Epithelial Epithelial Cells Equilibrium Erythroid Experimental Models Exposure to Family Functional disorder Goals HIV HIV Envelope Protein gp120 HIV-1 Health Host Defense Human Immune Immune response Immunoglobulins Impairment Individual Infection Inflammatory Injury Innate Immune Response Lung Lung diseases Lung immune response Lymphoid Tissue Molecular Myeloid Cells Natural Immunity Nuclear Oxidation-Reduction Oxidative Stress Pneumonia Population Predisposition Proteins Pseudomonas aeruginosa Pulmonary Inflammation Risk Rodent Model Signal Transduction System Testing Time Tissues Transgenic Animals Transgenic Mice Transgenic Organisms Translating Viral Load result Viral Proteins Viral reservoir Virus Virus Latency Virus Replication Wild Type Mouse activating transcription factor airway epithelium alveolar epithelium antiretroviral therapy chronic infection clinically relevant immune function improved in vivo lung health lung injury macrophage member novel novel strategies novel therapeutic intervention receptor response tat Protein therapeutic development tool

项目摘要

Infection by the human immunodeficiency virus (HIV) remains a major global threat with ~34 million individuals living with HIV worldwide. Although combination antiretroviral therapy is effective at slowing disease progression, it fails to eradicate latent viral reservoirs. In parallel, HIV integrates into target tissues and the chronic expression of HIV-related proteins, including gp120 and Tat, can induce alveolar macrophage and epithelial dysfunction even when ART limits viral replication to undetectably low levels. Consequently, individuals living with HIV are remarkably susceptible (perhaps 10-fold or greater) to serious pneumonias, such as from Pseudomonas aeruginosa, and lung injury. Using clinically relevant HIV-1 transgenic rodent models and cell culture systems we discovered that HIV-related proteins induce oxidative stress by inhibiting Nrf2 (Nuclear factor (erythroid-derived 2)-like 2), the master transcription factor that activates anti-oxidant and immune defenses. Our preliminary studies for the first time show that HIV-1 transgenic mice have an impaired clearance of P. aeruginosa with exacerbated lung injury and inflammation compared to wild type mice. Additionally, the relative loss of Nrf2 signaling results in unrestrained inflammatory signaling in macrophages including the activation of Triggering Receptor Expressed on Myeloid cells-1 (TREM-1), a member of the super immunoglobulin family expressed on myeloid cells. These intriguing findings led us to hypothesize that chronic exposure to HIV-related viral proteins dysregulates the normal balance between Nrf2 and TREM-1 signaling. This imbalance, in which Nrf2 is suppressed and TREM-1 is induced, promotes a pathophysiological environment that impairs innate immune responses to bacterial invasion and renders the lung susceptible to infection and injury. We further hypothesize that targeting the balance between Nrf2 and TREM-1 signaling is a novel therapeutic approach to enhance lung health in individuals living with HIV. We propose to test these hypotheses in three integrated aims: 1) Investigate the molecular basis for the dysfunctional signaling of Nrf2 and TREM-1 in macrophages in response to HIV-related viral proteins. 2) Define the functional consequences of TREM-1 induction in alveolar macrophages by HIV-related proteins on both epithelial barrier integrity and macrophage-epithelial interactive innate immunity against Pseudomonas aeruginosa. 3) Determine the impact of modulating Nrf2-TREM-1 signaling in vivo on lung bacterial clearance in HIV-1 transgenic mice challenged with Pseudomonas aeruginosa. It is imperative that we elucidate the mechanisms by which HIV-related proteins impair innate immunity within the lung, including how they promote an environment in which latent viral reservoirs may be established within the alveolar macrophage pool. In parallel, understanding the discrete molecular and cellular mechanisms by which HIV-related proteins impair alveolar macrophage immune responses and the associated integrity of the alveolar epithelial barrier will provide novel findings that can guide the development of therapeutic strategies to enhance lung health in individuals living with HIV.

人类免疫缺陷病毒（HIV）感染仍然是全球面临的主要威胁，约有3400万人感染HIV。艾滋病病毒感染者虽然联合抗逆转录病毒疗法在减缓疾病方面是有效的，进展，它未能根除潜伏的病毒储库。与此同时，HIV整合到靶组织中， HIV相关蛋白，包括gp 120和达特，的慢性表达可诱导肺泡巨噬细胞和即使ART将病毒复制限制在不可检测的低水平，也会导致上皮功能障碍。因此，委员会认为，艾滋病毒感染者非常容易（可能是10倍或更高）患严重肺炎，铜绿假单胞菌和肺损伤。使用临床相关的HIV-1转基因啮齿动物模型在细胞培养系统中，我们发现HIV相关蛋白通过抑制Nrf 2 （核因子（红细胞衍生2）样2），激活抗氧化剂和抗氧化剂的主转录因子，免疫防御我们的初步研究首次表明，HIV-1转基因小鼠具有受损的与野生型小鼠相比，铜绿假单胞菌的清除加剧了肺损伤和炎症。此外，Nrf 2信号传导的相对损失导致巨噬细胞中不受限制的炎症信号传导包括髓样细胞表达的触发受体-1（TREM-1）的激活，TREM-1是超巨噬细胞的成员。免疫球蛋白家族在骨髓细胞上表达。这些有趣的发现使我们假设，暴露于HIV相关的病毒蛋白质使Nrf 2和TREM-1信号传导之间的正常平衡失调。这种不平衡，其中Nrf 2被抑制而TREM-1被诱导，促进了病理生理学的不平衡。环境，损害对细菌入侵的先天免疫反应，并使肺易受感染和损伤。我们进一步假设，靶向Nrf 2和TREM-1信号传导之间的平衡，一种新的治疗方法，以提高艾滋病毒感染者的肺部健康。我们建议测试这些本研究的主要目的是：1）研究Nrf 2信号传导功能障碍的分子基础和TREM-1在巨噬细胞中对HIV相关病毒蛋白的应答。2)定义功能性后果 HIV相关蛋白在肺泡巨噬细胞中诱导TREM-1对上皮屏障完整性和巨噬细胞-上皮细胞相互作用的天然免疫对铜绿假单胞菌。3)确定影响在体内调节Nrf 2-TREM-1信号传导对HIV-1转基因小鼠激发的肺细菌清除的影响铜绿假单胞菌我们必须阐明艾滋病毒相关的蛋白质损害肺内的先天免疫，包括它们如何促进潜伏性免疫的环境。可以在肺泡巨噬细胞池内建立病毒储库。与此同时，理解离散 HIV相关蛋白损害肺泡巨噬细胞免疫的分子和细胞机制反应和相关的肺泡上皮屏障的完整性将提供新的发现，指导制定治疗策略，以增强艾滋病毒感染者的肺部健康。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

UPR modulation of host immunity by Pseudomonas aeruginosa in cystic fibrosis.

DOI：
10.1042/cs20200066
发表时间：
2020-07-31
期刊：
Clinical science (London, England : 1979)
影响因子：
0
作者：
Bedi B;Lin KC;Maurice NM;Yuan Z;Bijli K;Koval M;Hart CM;Goldberg JB;Stecenko A;Sadikot RT
通讯作者：
Sadikot RT

Bacterial Pathogens Causing Pneumonia Post Hematopoietic Stem Cell Transplant: The Chronic GVHD Population.

DOI：
10.3390/pathogens12050726
发表时间：
2023-05-17
期刊：
Pathogens (Basel, Switzerland)
影响因子：
0
作者：
Chaaban S;Zimmer A;Bhatt VR;Schmidt C;Sadikot RT
通讯作者：
Sadikot RT

Plasma Sphingomyelin Disturbances: Unveiling Its Dual Role as a Crucial Immunopathological Factor and a Severity Prognostic Biomarker in COVID-19.

DOI：
10.3390/cells12151938
发表时间：
2023-07-26
期刊：
CELLS
影响因子：
6
作者：
Toro, Diana Mota V.;da Silva-Neto, Pedro V.;de Carvalho, Jonatan C. S. A.;Fuzo, Carlos A. M.;Perez, Malena M.;Pimentel, Vinicius E.;Fraga-Silva, Thais F. C.;Oliveira, Camilla N. S. R.;Caruso, Glaucia R.;Vilela, Adriana F. L.;Nobre-Azevedo, Pedro V.;Defelippo-Felippe, Thiago V.;Argolo, Jamille G. M. M.;Degiovani, Augusto M.;Ostini, Fatima M. R.;Feitosa, Marley R. S.;Parra, Rogerio S. C.;Vilar, Fernando C. G.;Gaspar, Gilberto G.;da Rocha, Jose J. R.;Feres, Omar P.;Costa, Gabriel P.;Maruyama, Sandra R. C.;Russo, Elisa M. S.;Fernandes, Ana Paula M.;Santos, Isabel K. F. M.;Malheiro, Adriana T.;Sadikot, Ruxana T.;Bonato, Vania L. D.;Cardoso, Cristina R. B.;Dias-Baruffi, Marcelo;Trape, Atila A.;Faccioli, Lucia H. A.;Sorgi, Carlos A.
通讯作者：
Sorgi, Carlos A.

MicroRNA-155 Modulates Macrophages' Response to Non-Tuberculous Mycobacteria through COX-2/PGE2 Signaling.