Decoding mutualistic microbiota-B cell interactions in the HIV-1-infected gut: impact on immunological non-responders
Decoding mutualistic microbiota-B cell interactions in the HIV-1-infected gut: impact on immunological non-responders
批准号:
10626870
负责人:
ANDREA CERUTTI
金额:
$82.3万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
未结题
起止时间:
2020-05-07 至 2025-04-30
关键词:
3-DimensionalArchitectureAutomobile DrivingB-LymphocytesBacteroidesBiological AssayBiologyBloodCell CommunicationCell OntogenyCellsDNADiseaseDisease OutcomeDissectionElementsFaithFeedbackFlow CytometryGastroenterologistGastrointestinal tract structureGerm-FreeGnotobioticGoalsGut MucosaHIVHIV-1IgA1IgA2ImmuneImmune responseImmune systemImmunofluorescence MicroscopyImmunoglobulin AImmunohistochemistryImmunologicsImpairmentIndividualInfectionInflammationInflammatoryInterleukin-6InternationalInterruptionIntestinesLesionLongitudinal StudiesMeasuresMetagenomicsMethodologyMethodsMucosal Immune SystemMucosal ImmunityMucous MembraneMusPathogenesisPatientsPenetrancePhenotypePhysiologicalPopulationProductionPropertyRegulationResearchResearch PersonnelSeminalSerumSignal TransductionTNF geneTestingTherapeuticTissuesTrainingViralViral PathogenesisViral reservoirVirionVirus Replicationantiretroviral therapycohortcommensal bacteriacommunity settingdysbiosisepithelial injuryexperiencefecal microbiomefecal microbiotagastrointestinalgut bacteriagut inflammationgut microbiomegut microbiotahealthy volunteerhost microbiotaimmune functionimmune reconstitutioninsightintestinal epitheliumintestinal fatty acid binding proteinmedical schoolsmembermicrobialmicrobial communitymicrobiomemicrobiome researchmicrobiotanovelpatient subsetsprogramsrecruitresponsesynergismviral RNA
中文摘要
项目摘要
肠道微生物组、粘膜免疫细胞和HIV-1病毒粒子通过密切的相互作用影响彼此的功能。
和多方面的相互作用,决定感染者的疾病结果。在这个多PI提案中,
我们将检验HIV-1感染引起粘膜免疫系统严重破坏的中心假设,
在开始联合抗逆转录病毒治疗(cART)后,该系统未消退。通过
HIV-1阻断了微生物群和宿主免疫系统之间的关键信号,
导致生态失调的免疫改变后者触发了一个自我延续的、适应不良的反馈回路
它损害病毒准种的调节,促进HIV-1病毒粒子在肠道的持久存在,
在开始cART后,患者亚组的免疫重建不理想。的目的
这项研究计划将通过一个独特的合作努力,涉及三个高度
互补群体。Saurabh Mehandru博士,PI,是一名训练有素的胃肠病学家,拥有超过15年的经验,
在HIV-1感染领域的经验及其对粘膜免疫影响的几项关键贡献。他
将招募受感染的受试者,获得肠道组织,并沿着沿着描绘肠道和全身免疫群体。
HIV-1在肠道中的储存库(目标1)。Andrea Cerutti博士,联合PI,是世界知名的生物学专家,
来自健康和HIV-1感染个体的粘膜B细胞。他将研究肠道伊加反应,
HIV-1感染的肠粘膜,重点是B细胞个体发育,克隆型结构和细菌反应性,
IgA 1和IgA 2亚类。他还将定义不平衡的IgA 1和IgA 2反应对微生物的影响。
易位,肠道炎症和HIV-1复制(目的2)。Jeremiah Faith,Co-PI,是一位国际
他是微生物组研究领域公认的领导者,对该领域做出了几项开创性贡献。他将描述
HIV-1诱导的肠道微生物组改变及其对HIV-1诱导的粘膜伊加扰动的影响
他还将使用携带HIV-1感染患者或健康对照的肠道微生物群的gnotobiotic小鼠
测试cART对肠道细菌的影响,与宿主疾病状态无关(目的3)。
英文摘要
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).
期刊论文(1)
专著(0)
科研奖励(0)
会议论文
DOI:
10.1053/j.gastro.2020.09.029
发表时间:
2021-01
期刊:
Gastroenterology
影响因子:
29.4
作者:
[Suárez-Fariñas M, Tokuyama M, Wei G, Huang R, Livanos A, Jha D, Levescot A, Irizar H, Kosoy R, Cording S, Wang W, Losic B, Ungaro RC, Di'Narzo A, Martinez-Delgado G, Suprun M, Corley MJ, Stojmirovic A, Houten SM, Peters L, Curran M, Brodmerkel C, Perrigoue J, Friedman JR, Hao K, Schadt EE, Zhu J, Ko HM, Cho J, Dubinsky MC, Sands BE, Ndhlovu L, Cerf-Bensusan N, Kasarskis A, Colombel JF, Harpaz N, Argmann C, Mehandru S]
通讯作者:
Mehandru S
Decoding mutualistic microbiota-B cell interactions in the HIV-1-infected gut: impact on immunological non-responders
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批准号:10414937
-
项目类别:
-
资助金额:$82.3万
-
财政年份:2020
-
负责人:ANDREA CERUTTI
-
依托单位:
Decoding mutualistic microbiota-B cell interactions in the HIV-1-infected gut: impact on immunological non-responders
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批准号:9894545
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项目类别:
-
资助金额:$82.3万
-
财政年份:2020
-
负责人:ANDREA CERUTTI
-
依托单位:
Decoding mutualistic microbiota-B cell interactions in the HIV-1-infected gut: impact on immunological non-responders
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批准号:10160898
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项目类别:
-
资助金额:$82.3万
-
财政年份:2020
-
负责人:ANDREA CERUTTI
-
依托单位:
Dissecting The Interplay of GM-CSF and Neutrophils In IgG and IgA Responses
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批准号:8516868
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项目类别:
-
资助金额:$66.38万
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财政年份:2013
-
负责人:ANDREA CERUTTI
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依托单位:
Regulation and Function of Immunoglobulin D in Mucosal Immune Defense
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批准号:8508845
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项目类别:
-
资助金额:$41.53万
-
财政年份:2011
-
负责人:ANDREA CERUTTI
-
依托单位:
Dissecting The Interplay of GM-CSF and Neutrophils In IgG and IgA Responses
-
批准号:8198166
-
项目类别:
-
资助金额:$64.22万
-
财政年份:2011
-
负责人:ANDREA CERUTTI
-
依托单位:
Regulation and Function of Immunoglobulin D in Mucosal Immune Defense
-
批准号:8296171
-
项目类别:
-
资助金额:$41.53万
-
财政年份:2011
-
负责人:ANDREA CERUTTI
-
依托单位:
Regulation and Function of Immunoglobulin D in Mucosal Immune Defense
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批准号:8180217
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项目类别:
-
资助金额:$42.38万
-
财政年份:2011
-
负责人:ANDREA CERUTTI
-
依托单位:
Regulation of antibody diversification and production in HIV-1 infection
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批准号:8050194
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项目类别:
-
资助金额:$41.53万
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财政年份:2008
-
负责人:ANDREA CERUTTI
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依托单位:
Regulation of antibody diversification and production in HIV-1 infection
-
批准号:7586170
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项目类别:
-
资助金额:$42.0万
-
财政年份:2008
-
负责人:ANDREA CERUTTI
-
依托单位:
Regulation of antibody diversification and production in HIV-1 infection
-
批准号:8083734
-
项目类别:
-
资助金额:$41.95万
-
财政年份:2008
-
负责人:ANDREA CERUTTI
-
依托单位:
Regulation of antibody diversification and production in HIV-1 infection
-
批准号:8259418
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项目类别:
-
资助金额:$41.53万
-
财政年份:2008
-
负责人:ANDREA CERUTTI
-
依托单位:
Regulation of antibody diversification and production in HIV-1 infection
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批准号:7495309
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项目类别:
-
资助金额:$42.0万
-
财政年份:2008
-
负责人:ANDREA CERUTTI
-
依托单位:
Regulation of antibody production by innate immune cells
-
批准号:6928075
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项目类别:
-
资助金额:$42.0万
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财政年份:2005
-
负责人:ANDREA CERUTTI
-
依托单位:
Regulation of antibody production by innate immune cells
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批准号:7188607
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项目类别:
-
资助金额:$56.62万
-
财政年份:2005
-
负责人:ANDREA CERUTTI
-
依托单位:
Regulation of antibody production by innate signals
-
批准号:8584273
-
项目类别:
-
资助金额:$42.38万
-
财政年份:2005
-
负责人:ANDREA CERUTTI
-
依托单位:
Regulation of antibody production by innate signals
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批准号:8237267
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项目类别:
-
资助金额:$42.38万
-
财政年份:2005
-
负责人:ANDREA CERUTTI
-
依托单位:
Regulation of antibody production by innate signals
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批准号:8390467
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项目类别:
-
资助金额:$39.83万
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财政年份:2005
-
负责人:ANDREA CERUTTI
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依托单位:
Regulation of antibody production by innate immune cells
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批准号:7030980
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项目类别:
-
资助金额:$41.01万
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财政年份:2005
-
负责人:ANDREA CERUTTI
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依托单位:
Regulation of antibody production by innate immune cells
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批准号:7404472
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项目类别:
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资助金额:$39.07万
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财政年份:2005
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负责人:ANDREA CERUTTI
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依托单位:
海外基金