Decoding mutualistic microbiota-B cell interactions in the HIV-1-infected gut: impact on immunological non-responders

解码 HIV-1 感染肠道中微生物群与 B 细胞相互作用：对免疫无反应者的影响

基本信息

批准号：
10414937
负责人：
ANDREA CERUTTI
金额：
$ 82.3万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-07 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10414937
关键词：
3-Dimensional Architecture Automobile Driving B-Lymphocytes Bacteroides Biological Assay Biology Blood Cell Communication Cell Ontogeny Cells Communities DNA Disease Disease Outcome Dissection Elements Feedback Flow Cytometry Gastroenterologist Gastrointestinal tract structure Germ-Free Gnotobiotic Goals Gut Mucosa HIV HIV-1 IgA1 IgA2 Immune Immune response Immune system Immunofluorescence Microscopy Immunoglobulin A Immunohistochemistry Immunologics Impairment Individual Infection Inflammation Inflammatory Interleukin-6 International Interruption Intestines Lesion Longitudinal Studies Measures Metagenomics Methodology Methods Mucosal Immune System Mucosal Immunity Mucous Membrane Mus Pathogenesis Patients Penetrance Phenotype Physiological Population Production Property Regulation Research Research Personnel Seminal Serum Signal Transduction TNF gene Testing Therapeutic Tissues Training Viral Viral Pathogenesis Viral reservoir Virion Virus Replication antiretroviral therapy cohort commensal bacteria dysbiosis epithelial injury experience fecal microbiome fecal microbiota gastrointestinal gut bacteria gut inflammation gut microbiome gut microbiota healthy volunteer host microbiota immune function immune reconstitution insight intestinal epithelium intestinal fatty acid binding protein medical schools member microbial microbial community microbiome microbiome research microbiota novel patient subsets programs recruit response synergism viral RNA

项目摘要

Project Summary The gut microbiome, mucosal immune cells and HIV-1 virions influence each other's functions through intimate and multifaceted interactions that determine disease outcomes in infected individuals. In this multi-PI proposal, we will test the central hypothesis that HIV-1 infection causes a profound disruption of the mucosal immune system, which does not resolve following the initiation of combination antiretroviral therapy (cART). By interrupting key signals between the microbiota and the host's immune system, HIV-1 elicits profound intestinal immune alterations that cause dysbiosis. This latter triggers a self-perpetuating, maladaptive feedback loop that impairs the regulation of viral quasispecies, promotes intestinal persistence of HIV-1 virions and, in a subset of patients, causes suboptimal immunological reconstitution following initiation of cART. The aims of this research program will be achieved through a unique collaborative effort involving three highly complementary groups. Dr. Saurabh Mehandru, PI, is a trained gastroenterologist with more than 15 years of experience in the field of HIV-1 infection and several key contributions on its impact in mucosal immunity. He will recruit infected subjects, obtain gut tissue, and profile intestinal and systemic immune populations along with HIV-1 reservoirs in the gut (Aim 1). Dr. Andrea Cerutti, Co-PI, is a world-renowned expert in the biology of mucosal B cells from both healthy and HIV-1-infected individuals. He will study intestinal IgA responses in the HIV-1-infected gut mucosa, focusing on the B cell ontogeny, clonotypic architecture and bacterial reactivity of IgA1 and IgA2 subclasses. He will also define the impact of unbalanced IgA1 and IgA2 responses on microbial translocation, gut inflammation and HIV-1 replication (Aim 2). Dr. Jeremiah Faith, Co-PI, is an internationally recognized leader in microbiome research, with several seminal contributions to this field. He will characterize HIV-1-induced alterations of the gut microbiome and their impact on HIV-1-induced mucosal IgA perturbations. He will also use gnotobiotic mice harboring the gut microbiota from HIV-1-infected patients or healthy controls to test the impact of cART on intestinal commensal bacteria independently of the host disease status (Aim 3).