Host and Pathogen Diversity in Mtb and SIV Infection

Mtb 和 SIV 感染的宿主和病原体多样性

基本信息

批准号：
9203710
负责人：
Philana Ling Lin
金额：
$ 18.98万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9203710
关键词：
Accounting Acquired Immunodeficiency Syndrome Animal Model Animals Anti-Retroviral Agents Bacteria Breathing Cause of Death Cells Cessation of life Clinical Trials Complex DNA Data Disease Emigrations Event Evolution Funding Goals Granuloma Growth HIV HIV Infections Heterogeneity High Prevalence Human Immune Immune response Immune system Individual Infection Infection Control Infection prevention Lead Lesion Licensing Lung Lymphoid Cell Measures Mediastinal lymph node group Messenger RNA Minority Morbidity - disease rate Mucosal Immune Responses Mycobacterium tuberculosis Outcome Patient-Focused Outcomes Patients Peripheral Plasma Play RNA Risk Role SIV Sampling Severities Site T-Lymphocyte Time Tissues Treatment Protocols Tuberculosis Vaccines Viral Viral reservoir Virus Replication aerosolized co-infection design env Genes extracellular genome sequencing global health high risk improved insight killings latent infection macrophage mortality next generation next generation sequencing novel novel vaccines pathogen pulmonary granuloma response tool treatment strategy

项目摘要

Project Summary As individual pathogens, tuberculosis (TB) and HIV infection are the leading infectious causes of death worldwide. The 1.5 million deaths from TB in 2014 account for only 5-10% of people infected with M. tuberculosis (Mtb), the bacteria that causes TB. This underscores the high prevalence of this infection that occurs by inhalation of the bacteria via aerosolized droplets. Co-infection with Mtb and HIV represent a “deadly synergy”: During HIV infection, the peak of the viral set point and degree of viral heterogeneity is associated with poor outcome and patients with HIV-Mtb co-infection have been well recognized to have greater viral set points, diversity and faster progression to AIDS. Similarly, patients with Mtb-HIV co-infection have a higher risk of TB disease, reactivation TB and reinfection compared to those with Mtb alone. In our preliminary data, we show that the immune profiles of the airway cells are associated with the initial response to infection and outcome in an animal model that mimics human TB. These responses however, have not been fully characterized. We hypothesize that the early mucosal immune responses in the airway play important roles in the control of Mtb infection and this response is impaired during SIV (an HIV surrogate) infection. This proposal will leverage samples from already funded studies using an animal model that mimics both human Mtb and HIV infection (using SIV as a surrogate). In these studies, serial samples obtained before and during Mtb infection as well as subsequent SIV infection will be used. In Aim 1, we will identify signatures of airway protection against severe forms of TB during Mtb infection and SIV-Mtb co-infection. This will be done with a uniquely designed set of tools that profile innate and early adaptive mRNA transcriptional profiles. We will also better characterize innate lymphoid cells in the airways during the course of Mtb and SIV-Mtb co-infection. Data are emerging that viral divergence and evolution can occur in localized sites of co-infection. We hypothesize that localized sites of Mtb involvement (e.g., granulomas) in the lung and mediastinal lymph nodes can facilitate viral reservoirs where SIV viral growth and divergence can occur that ultimately leads to viral progression. In Aim 2, we will characterize the distribution of SIV viral diversity within and among Mtb specific lesions as well as peripheral sites of SIV involvement using MiSeq next generation and ultra- deep single genome sequencing. Results from these studies will reveal new innate and adaptive mechanisms of protection against severe forms of Mtb infection and how these are altered during SIV-Mtb co-infection that could ultimately be harnessed into new vaccine strategies. We will also characterized the depth of viral diversity within the SIV-Mtb co-infected host that could ultimately lead to better treatment strategies to limit the morbidity and mortality of these two pathogens.

项目摘要作为个体病原体，结核病（TB）和HIV感染是主要的感染原因全球死亡。 2014年结核病的150万人死亡仅占感染者的5-10％与结核分枝杆菌（MTB）一起，导致结核病的细菌。这强调了这一点的高流行通过雾化液滴吸入细菌而发生的感染。与MTB共同感染艾滋病毒代表“致命的协同作用”：在艾滋病毒感染期间，病毒设定点的峰值和程度病毒异质性与预后不佳有关，HIV-MTB共感染患者已经众所周知，具有更大的病毒设定点，多样性和更快的艾滋病发展。相似地， MTB-HIV共感染患者患结核病，重新激活和再感染的风险更高与单独使用MTB的人相比。在我们的初步数据中，我们表明了气道细胞与动物模型中对感染和结果的初始反应有关模仿人类结核。但是，这些响应尚未完全表征。我们假设气道中的早期粘膜免疫反应在MTB的控制中起重要作用在SIV（HIV替代）感染期间，感染和该反应受损。该提议将使用模仿人类MTB的动物模型利用已经资助的研究的样品和HIV感染（使用SIV作为替代物）。在这些研究中，在之前获得的连续样品在MTB感染期间以及随后的SIV感染期间。在AIM 1中，我们将确定在MTB感染和SIV-MTB期间，气道保护防止严重的结核病签名共同感染。这将使用一套独特设计的工具来完成，这些工具介绍了先天和早期自适应mRNA转录曲线。我们还将更好地表征先天淋巴样细胞 MTB和SIV-MTB共同感染过程中的气道。数据正在出现病毒差异并且进化可能发生在共同感染的局部位置中。我们假设MTB的局部位置参与肺和纵隔淋巴结中的参与（例如肉芽肿）可以促进病毒储量 SIV病毒生长和发散最终导致病毒进展的地方。在AIM 2中，我们将表征MTB特定内部和MTB内部SIV病毒多样性的分布病变以及使用Miseq下一代和超大型的SIV参与的外围部位深单基因组测序。这些研究的结果将揭示新的先天和自适应防御严重形式的MTB感染的机制以及如何改变它们 SIV-MTB共同感染最终可以利用为新的疫苗策略。我们也会表征了SIV-MTB共同感染的宿主内病毒多样性的深度，这些宿主最终可以领导更好的治疗策略以限制这两种病原体的发病率和死亡率。