Resistance to MTB infection in HIV infected individuals in Uganda and S. Africa
乌干达和南非 HIV 感染者对 MTB 感染的抵抗力
基本信息
- 批准号:9925746
- 负责人:
- 金额:$ 185.4万
- 依托单位:
- 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:2016-06-01 至 2022-05-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdultAfricaAlveolar MacrophagesBiologicalBiological AssayBiological MarkersBloodCD4 Positive T LymphocytesCRISPR/Cas technologyCell CountCellsClinicalCommunicable DiseasesComputing MethodologiesDataDiseaseEmploymentEpidemiologistExposure toFlow CytometryFred Hutchinson Cancer Research CenterGene Expression ProfileGenesGenetic TranscriptionGrowthHIVHIV InfectionsHIV-1HIV/TBHospitalsHost resistanceHouseholdHumanImmune responseImmunologistIndividualInnate Immune ResponseInstitutesIntegration Host FactorsInterferonsKnock-outLungMeasuresMiningMononuclearMycobacterium tuberculosisNatural ImmunityPathogenesisPathway interactionsPersonsPhagocytesPhenotypePhysiciansPlasmaPopulationRecording of previous eventsResistanceSouth AfricaSystemSystems BiologyT-LymphocyteTuberculin TestTuberculosisTuberculosis VaccinesUgandaUniversitiesViral Load resultWashingtonWhole Bloodaerosolizedantiretroviral therapyclinical phenotypeclinical research sitecohortexperiencefollow-upgenome-wide linkageinnate immune functioninsightmacrophagemonocytemultidisciplinarynovel strategiespathogenperipheral bloodpressurepublic health relevancerecruitresistance mechanismresponsesmall molecule inhibitortranscriptome sequencinguptake
项目摘要
DESCRIPTION (provided by applicant):
PROJECT SUMMARY Most people heavily exposed to Mycobacterium tuberculosis become infected and develop latent Mtb infection. However, in a TB contact study in urban Uganda, approximately 9% of close adult contacts did not develop LTBI during two years of follow-up. In S. Africa, some miners do not develop LTBI despite more than 20 years of employment under the highest Mtb infection pressure in the world. These persons without evidence of LTBI despite intense Mtb exposure appear to be LTBI resisters (RSTRs). Monocytes after Mtb infection revealed transcriptional signatures that distinguished RSTRs from HHC with LTBI. These data support the hypothesis that host factors can distinguish RSTRs and that they have protective innate immune responses expressed in macrophages. HIV dysregulates immune responses to Mtb, thus HIV infected persons depend more on innate immunity to control Mtb than HIV- persons. Thus we hypothesize that innate mechanisms of resistance to LTBI are more readily identified in HIV+ RSTRs. The aims are: 1. Identify, characterize and recruit cohorts of HIV+ individuals who resist latent Mtb infection among TB household contacts in Uganda and among miners in South Africa. Approach: Follow-up previously identified HIV+ RSTRs and recruit new RSTRs from among TB HHC in Uganda, and i S. Africa recruit a new cohort of HIV+ RSTRs. HIV+ LTBIs, and HIV- RSTRs and HIV- LTBIs will serve as controls. Hypothesis: HIV+ and HIV- RSTRs can be identified in populations with different Mtb exposures but host resistance mechanisms will be shared and thus enable assembly of robust cohorts for innate immune function studies. Aim 2. Determine macrophage transcriptional signatures associated with resistance to latent Mtb infection in HIV+ persons. Approach: Compare early transcriptional responses to Mtb in macrophages between HIV+ RSTRs and LTBIs. Compare these to the responses of macrophages from HIV- RSTRs and HIV- LTBIs, and extend studies to alveolar macrophages. Hypothesis: Biological pathways in macrophages regulate resistance to Mtb infection and these pathways are more readily identified in HIV+ persons. Aim 3. Determine cellular mechanisms of resistance to latent Mtb infection. Approach: a. Cellular knockouts through CRISPR/Cas9 technology and small molecule inhibitors to investigate how key genes and pathways identified in Aim 2 allow macrophages to resist or clear Mtb; b. Whole blood assays of Mtb killing to distinguish HIV+ RSTRs from LTBIs; c. Flow cytometry to examine whether innate unconventional T-cells are enriched in HIV+ RSTRs. Hypothesis: a. HIV+ RSTR use macrophage-specific pathways to control Mtb; b. A WBA can detect differences in control of Mtb growth between RSTRs and LTBIs; c. HIV+ RSTRs use unconventional innate T cells to control Mtb. For this project, we have assembled two experienced TB clinical research sites (Mulago Hospital in Uganda & the Aurum Institute in S. Africa) with epidemiologists, systems biologists, geneticists, immunologists, microbiologists, and clinicians at Makerere University in Uganda, Aurum Institute in S. Africa, University of Washington and Case Western Reserve University.
描述(由申请人提供):
大多数严重暴露于结核分枝杆菌的人被感染并发展成潜伏性结核分枝杆菌感染。然而,在乌干达城市的一项结核病接触者研究中,约9%的密切成年接触者在两年的随访期间没有发生LTBI。In S.在非洲,尽管在世界上最高的结核病感染压力下工作了20多年,但一些矿工没有发展LTBI。这些人没有LTBI的证据,尽管强烈的结核分枝杆菌暴露似乎是LTBI抵抗者(RSTR)。Mtb感染后的单核细胞显示了将RSTR与具有LTBI的HHC区分开的转录特征。这些数据支持宿主因素可以区分RSTR并且它们在巨噬细胞中表达具有保护性先天免疫应答的假设。HIV使针对Mtb的免疫应答失调,因此HIV感染者比HIV-者更依赖于先天免疫来控制Mtb。因此,我们假设,先天机制的耐LTBI更容易确定在HIV+ RSTR。目标是:1.在乌干达的结核病家庭接触者和南非的矿工中,确定、描述和招募抵抗潜伏结核分枝杆菌感染的艾滋病毒阳性个体队列。方法:随访先前确定的HIV+ RSTR,并从乌干达的结核病HHC中招募新的RSTR,i S。非洲招募了一批新的艾滋病毒阳性RSTR。HIV+ LTBI、HIV-RSTR和HIV-LTBI将作为对照。假设:可以在具有不同Mtb暴露的人群中鉴定HIV+和HIV-RSTR,但宿主抗性机制将是共享的,从而能够组装用于先天免疫功能研究的稳健队列。目标2.确定巨噬细胞转录签名与艾滋病毒+人的潜伏性结核分枝杆菌感染的抵抗力。方法:比较HIV+ RSTR和LTBI之间巨噬细胞对Mtb的早期转录反应。将这些与来自HIV-RSTR和HIV-LTBI的巨噬细胞的反应进行比较,并将研究扩展到肺泡巨噬细胞。假设:巨噬细胞中的生物学途径调节对Mtb感染的抗性,并且这些途径在HIV+人群中更容易识别。目标3.确定对潜伏性Mtb感染的抗性的细胞机制。方法:a.通过CRISPR/Cas9技术和小分子抑制剂进行细胞敲除,以研究Aim 2中鉴定的关键基因和途径如何允许巨噬细胞抵抗或清除Mt B; B。Mtb杀伤的全血测定以区分HIV+ RSTR与LTBI; c.流式细胞术检查先天非常规T细胞是否富含HIV+ RSTR。假设:a. HIV+ RSTR使用巨噬细胞特异性途径来控制Mt B; B。WBA可以检测RSTR和LTBI之间Mtb生长控制的差异; c. HIV+ RSTR使用非常规的先天性T细胞来控制Mtb。在这个项目中,我们组建了两个有经验的结核病临床研究中心(乌干达的Mulago医院和南非的Aurum研究所)。非洲)与流行病学家,系统生物学家,遗传学家,免疫学家,微生物学家和临床医生在马凯雷雷大学在乌干达,奥鲁姆研究所在S。非洲、华盛顿大学和凯斯西储大学。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Importance of Study Design and Phenotype Definition in Ongoing Studies of Resistance to Latent Mycobacterium tuberculosis Infection.
研究设计和表型定义在正在进行的潜伏结核分枝杆菌感染耐药性研究中的重要性。
- DOI:10.1093/infdis/jiz539
- 发表时间:2020
- 期刊:
- 影响因子:0
- 作者:Stein,CatherineM;Mayanja-Kizza,Harriet;Hawn,ThomasR;Boom,WHenry
- 通讯作者:Boom,WHenry
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W. Henry Boom其他文献
W. Henry Boom的其他文献
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{{ truncateString('W. Henry Boom', 18)}}的其他基金
Epigenetic & Post-Translational Mechanisms of Macrophage Resistance to Mycobacterium tuberculosis During HIV Co-Infection
表观遗传
- 批准号:
10092518 - 财政年份:2018
- 资助金额:
$ 185.4万 - 项目类别:
Epigenetic & Post-Translational Mechanisms of Macrophage Resistance to Mycobacterium tuberculosis During HIV Co-Infection
表观遗传
- 批准号:
10385714 - 财政年份:2018
- 资助金额:
$ 185.4万 - 项目类别:
Microbiology and Immunology Training for HIV and HIV-Related Research in Uganda (MITHU)
乌干达艾滋病毒和艾滋病毒相关研究微生物学和免疫学培训 (MITHU)
- 批准号:
9253465 - 财政年份:2016
- 资助金额:
$ 185.4万 - 项目类别:
Microbiology and Immunology Training for HIV and HIV-Related Research in Uganda (MITHU)
乌干达艾滋病毒和艾滋病毒相关研究微生物学和免疫学培训 (MITHU)
- 批准号:
10243781 - 财政年份:2016
- 资助金额:
$ 185.4万 - 项目类别:
Microbiology and Immunology Training for HIV and HIV-Related Research in Uganda (MITHU)
乌干达艾滋病毒和艾滋病毒相关研究微生物学和免疫学培训 (MITHU)
- 批准号:
10392513 - 财政年份:2016
- 资助金额:
$ 185.4万 - 项目类别:
Resistance to MTB infection in HIV infected individuals in Uganda and S. Africa
乌干达和南非 HIV 感染者对 MTB 感染的抵抗力
- 批准号:
9495556 - 财政年份:2016
- 资助金额:
$ 185.4万 - 项目类别:
Microbiology and Immunology Training for HIV and HIV-Related Research in Uganda (MITHU)
乌干达艾滋病毒和艾滋病毒相关研究微生物学和免疫学培训 (MITHU)
- 批准号:
9437863 - 财政年份:2016
- 资助金额:
$ 185.4万 - 项目类别:
Microbiology and Immunology Training for HIV and HIV-Related Research in Uganda (MITHU)
乌干达艾滋病毒和艾滋病毒相关研究微生物学和免疫学培训 (MITHU)
- 批准号:
10592269 - 财政年份:2016
- 资助金额:
$ 185.4万 - 项目类别:
Microbiology and Immunology Training for HIV and HIV-Related Research in Uganda (MITHU)
乌干达艾滋病毒和艾滋病毒相关研究微生物学和免疫学培训 (MITHU)
- 批准号:
9545389 - 财政年份:2016
- 资助金额:
$ 185.4万 - 项目类别:
Natural Resistance to Mycobacterium Tuberculosis Infection
对结核分枝杆菌感染的天然抵抗力
- 批准号:
8819988 - 财政年份:2015
- 资助金额:
$ 185.4万 - 项目类别:
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