Mapping of the IgM and IgG antibody responses to Talaromyces marneffei infection in mice and humans - Deciphering acute from reactivated or latent infections
小鼠和人类对马尔尼菲踝节菌感染的 IgM 和 IgG 抗体反应图谱 - 区分急性感染和潜伏感染
基本信息
- 批准号:10327068
- 负责人:
- 金额:$ 23.24万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-06-22 至 2023-05-31
- 项目状态:已结题
- 来源:
- 关键词:Acquired Immunodeficiency SyndromeAcuteAmphotericin BAntibodiesAntibody ResponseAntifungal TherapyCase-Control StudiesCessation of lifeChinaClinicalClinical TrialsCountryCryptococcosisDataDetectionDiagnosisDiagnosticDiseaseDisease ManagementEnzyme ImmunoassayEpidemiologyGoalsHIVHumanImmigrantImmune responseImmune systemImmunocompetentImmunoglobulin GImmunoglobulin MIncidenceIndividualInfectionIntegration Host FactorsItraconazoleKnowledgeLungMapsModelingMonoclonal AntibodiesMusOpportunistic InfectionsOpticsOropharyngealOutcomePathogenesisPatient-Focused OutcomesPatientsPatternPersonsPlasmaPopulationPrevalencePrevention strategyPrimary InfectionResearchResearch DesignRiskSamplingSerodiagnosesSerologySerology testSeroprevalencesSoutheastern AsiaSyndromeTalaromycesTestingTimeTransplantationTuberculosisVietnamVirulentWorkacute infectionanimal model developmentantibody testbasebiobankburden of illnesscase controlchemotherapychronic infectioncohortdensitydiagnostic accuracydisorder controldisorder preventionepidemiology studyexperiencefungusgeographic riskhigh risklatent infectionmortalitymouse modelnovelpathogenpathogenic funguspopulation basedresponseseroconversion
项目摘要
Abstract
Talaromycosis is an invasive mycosis caused by the dimorphic fungus Talaromyces marneffei (Tm) endemic in
Southeast Asia. Infection kills one in three infected people with a compromised immune system, and is the
leading causes of HIV-associated death in the endemic region. Current diagnostics can only identify the fungus
in late stage infection. We know infection can reactivate up to 7 years from exposure in returning travelers, but
we lack an antibody test to determine who has been infected and who has a primary versus a reactivated
infection. We and other have documented a 30-70% increase in cases during the rainy humid months in multiple
countries. Our epidemiology studies suggest that this remarkable seasonality is due to acute exposure leading
to acute primary infections rather than alterations in host factors. Our human cohorts, including the IVAP clinical
trial, have shown that patients who present with an acute pulmonary syndrome have a shorter duration of illness
and rapidly progressive fatality. Our central hypothesis is that the acute pulmonary form of infection has a more
virulent pathogenesis than the reactivated form, and host IgM and IgG patterns can differentiate between these
forms. We propose two related but independent aims to test this hypothesis.
AIM 1. To validate the novel anti-Mp1p IgM and IgG enzyme immunoassay (EIA) and to delineate the
impact of acute primary infection on patient outcomes. Here, we will leverage the IVAP trial biorepository
with longitudinal plasma samples (6 timepoints collected over 24 weeks) from 440 culture-confirmed
talaromycosis patients to map the IgM and IgG responses in humans, identify the IgM/IgG serological pattern
associated with acute infection, and determine the impact of acute primary infection on patient outcomes.
AIM 2. To develop a novel murine pulmonary model to decipher the host anti-Tm antibody responses to
primary versus reactivated infection. Here, we will develop a novel pulmonary model using non-invasive
oropharyngeal aspiration and low infection inoculum to mimic natural human infection. We will develop an acute
primary infection model in CD4-depleted mice and develop chronic infection in immunocompetent mice, followed
by CD4 depletion to induce a reactivated infection model. Our goal is to understand how a mammalian antibody
response should differ between primary versus reactivated infection and use the mouse antibody data to
strengthen the interpretation of antibody responses in humans.
Impact. Our studies aim to establish a serological diagnosis for talaromycosis which has the potential to
differentiate acute from reactivated infection and expand our knowledge of disease spectrum. The new murine
pulmonary model will facilitate new research into the host immune response to Tm infection. The antibody test
will enable population-based seroprevalence studies to advance our understanding of disease burden,
geographic risk, latency, and risk populations. This knowledge will inform both disease management at the
individual level and prevention strategies at the population level.
摘要
塔拉霉菌病是一种侵袭性霉菌病,由马尔尼菲塔拉霉菌(TM)二相性真菌引起。
东南亚。感染会导致免疫系统受损的感染者中三分之一死亡,这是
在流行地区导致艾滋病毒相关死亡的主要原因。目前的诊断方法只能确定真菌
晚期感染。我们知道,在返回的旅行者中,感染可以在暴露后长达7年的时间内重新激活,但
我们缺乏抗体测试来确定谁被感染了,谁有初始的和重新激活的
感染。我们和其他人已经记录了在多雨潮湿的月份中,病例增加了30%-70%
国家。我们的流行病学研究表明,这种显著的季节性是由于急性接触导致的
与急性原发感染有关,而不是宿主因素的改变。我们的人类队列,包括IVAP临床
试验表明,患有急性肺综合征的患者病程较短。
和快速发展的死亡。我们的中心假设是急性肺部感染有更多的
致病毒力比重新激活的形式更强,而宿主的免疫球蛋白和免疫球蛋白模式可以区分这两种
表格。我们提出了两个相关但独立的目标来检验这一假说。
目的1.验证新型抗Mp1p-Ig M和Ig G双抗体夹心酶免疫分析法(EIA)的可行性。
急性原发感染对患者预后的影响。在这里,我们将利用IVAP试验生物资源库
使用来自440个培养确认的纵向血浆样本(在24周内收集了6个时间点)
对距菌病患者进行人类免疫球蛋白M和免疫球蛋白G反应图谱的绘制,确定免疫球蛋白/免疫球蛋白的血清学模式
与急性感染相关,并确定急性原发感染对患者预后的影响。
目的2.建立一种新的小鼠肺模型,以破译宿主抗TM抗体对
初次感染与再激活感染的对比。在这里,我们将开发一种新的肺模型,使用非侵入性
口咽抽吸和低感染疫苗,以模拟自然人类感染。我们将发展出一种急性
在CD4耗尽的小鼠中建立初始感染模型,并在免疫能力强的小鼠中发展成慢性感染,随后
通过耗尽CD_4诱导再激活的感染模型。我们的目标是了解哺乳动物抗体是如何
初次感染和再激活感染之间的反应应该不同,并使用小鼠抗体数据来
加强对人体抗体反应的解释。
冲击力。我们的研究旨在建立一种对距菌病的血清学诊断,这种病有可能
区分急性感染和重新激活的感染,扩大我们对疾病谱的了解。新的小鼠
肺模型有助于对TM感染后宿主免疫应答的新研究。抗体检测
将使基于人群的血清阳性率研究能够促进我们对疾病负担的理解,
地理风险、潜伏期和风险人群。这一知识将为疾病管理提供信息,
个人层面和人口层面的预防战略。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Thuy Le其他文献
Thuy Le的其他文献
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{{ truncateString('Thuy Le', 18)}}的其他基金
Tropical Medicine Research Center for Talaromycosis in Vietnam
越南踝部真菌病热带医学研究中心
- 批准号:
10444448 - 财政年份:2022
- 资助金额:
$ 23.24万 - 项目类别:
Tropical Medicine Research Center for Talaromycosis in Vietnam
越南踝部真菌病热带医学研究中心
- 批准号:
10598580 - 财政年份:2022
- 资助金额:
$ 23.24万 - 项目类别:
Mapping of the IgM and IgG antibody responses to Talaromyces marneffei infection in mice and humans - Deciphering acute from reactivated or latent infections
小鼠和人类对马尔尼菲踝节菌感染的 IgM 和 IgG 抗体反应图谱 - 区分急性感染和潜伏感染
- 批准号:
10436393 - 财政年份:2021
- 资助金额:
$ 23.24万 - 项目类别:
Making an early diagnosis of talaromycosis - an approach to reduce morbidity and mortality in advanced HIV disease in Southeast Asia
对踝部真菌病进行早期诊断——一种降低东南亚晚期艾滋病毒发病率和死亡率的方法
- 批准号:
9978703 - 财政年份:2019
- 资助金额:
$ 23.24万 - 项目类别:
Making an early diagnosis of talaromycosis - an approach to reduce morbidity and mortality in advanced HIV disease in Southeast Asia
对踝部真菌病进行早期诊断——一种降低东南亚晚期艾滋病毒发病率和死亡率的方法
- 批准号:
10190805 - 财政年份:2019
- 资助金额:
$ 23.24万 - 项目类别:
Making an early diagnosis of talaromycosis - an approach to reduce morbidity and mortality in advanced HIV disease in Southeast Asia
对踝部真菌病进行早期诊断——一种降低东南亚晚期艾滋病毒发病率和死亡率的方法
- 批准号:
10426172 - 财政年份:2019
- 资助金额:
$ 23.24万 - 项目类别:
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