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: 10327068
• 负责人: Thuy Le
• 金额: $ 23.24万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10327068
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Amphotericin B; Antibodies; Antibody Response; Antifungal Therapy; Case-Control Studies; Cessation of life; China; Clinical; Clinical Trials; Country; Cryptococcosis; Data; Detection; Diagnosis; Diagnostic; Disease; Disease Management; Enzyme Immunoassay; Epidemiology; Goals; HIV; Human; Immigrant; Immune response; Immune system; Immunocompetent; Immunoglobulin G; Immunoglobulin M; Incidence; Individual; Infection; Integration Host Factors; Itraconazole; Knowledge; Lung; Maps; Modeling; Monoclonal Antibodies; Mus; Opportunistic Infections; Optics; Oropharyngeal; Outcome; Pathogenesis; Patient-Focused Outcomes; Patients; Pattern; Persons; Plasma; Population; Prevalence; Prevention strategy; Primary Infection; Research; Research Design; Risk; Sampling; Serodiagnoses; Serology; Serology test; Seroprevalences; Southeastern Asia; Syndrome; Talaromyces; Testing; Time; Transplantation; Tuberculosis; Vietnam; Virulent; Work; acute infection; animal model development; antibody test; base; biobank; burden of illness; case control; chemotherapy; chronic infection; cohort; density; diagnostic accuracy; disorder control; disorder prevention; epidemiology study; experience; fungus; geographic risk; high risk; latent infection; mortality; mouse model; novel; pathogen; pathogenic fungus; population based; response; seroconversion

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.

抽象的 talomomycisis是由二态真菌塔拉罗斯（Talaromyces Marneffei）（tm）中流大流行引起的一种侵袭性真菌病。 东南亚。感染杀死三分之一的感染免疫系统的感染者，是 流行地区与HIV相关死亡的主要原因。当前的诊断只能识别真菌 在后期感染中。我们知道，感染可以在返回旅行者的情况下从暴露量中重新激活7年，但是 我们缺乏抗体测试来确定谁被感染，谁具有重新激活 感染。我们和其他人记录了多个雨季的案件增加了30-70％ 国家。我们的流行病学研究表明，这种非凡的季节性是由于急性暴露的领先 急性原发性感染，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，出现急性肺综合征的患者病情较短 和快速渐进的死亡。我们的中心假设是，急性肺部感染的形式更多 比重新激活形式的强度发病机理，宿主IgM和IgG模式可以区分这些发病机理 表格。我们提出了两个相关但独立的旨在检验这一假设的目标。 目标1。验证新型抗MP1P IgM和IgG酶免疫测定（EIA）并描绘 急性原发性感染对患者预后的影响。在这里，我们将利用IVAP试验生物验证 从440个培养证实的纵向等离子体样品（6周内收集了6个时点） 塔拉菌病患者绘制人类的IgM和IgG反应，识别IgM/IgG血清学模式 与急性感染相关，并确定急性原发性感染对患者预后的影响。 目标2。开发一种新型的鼠肺模型来破译宿主抗TM抗体反应 原发性感染与重新激活的感染。在这里，我们将使用非侵入性开发一种新型的肺模型 口咽抽吸和低感染接种对模仿天然人类感染。我们将发展一个敏锐的 CD4耗尽小鼠中的原发性感染模型，并在免疫能力小鼠中发展出慢性感染，随后 通过CD4耗竭来诱导重新激活的感染模型。我们的目标是了解哺乳动物抗体如何 原发性感染与重新激活的感染之间应有所不同，并使用小鼠抗体数据 加强对人类抗体反应的解释。 影响。我们的研究旨在建立talaromycisois的血清学诊断，有可能 将急性与重新激活感染区分开，并扩大我们对疾病谱的了解。新鼠 肺模型将促进对宿主免疫反应对TM感染的新研究。抗体测试 将使基于人群的血清阳性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。这些知识将为疾病管理提供信息 人口水平的个人水平和预防策略。