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 踝节菌病是一种侵袭性真菌病，由马尔尼菲踝节菌 (Tm) 引起，流行于 东南亚。感染导致三分之一免疫系统受损的感染者死亡，并且是 流行地区艾滋病毒相关死亡的主要原因。目前的诊断只能识别真菌 处于感染晚期。我们知道，回国旅行者接触病毒后长达 7 年内可能会重新激活感染，但是 我们缺乏抗体测试来确定谁已被感染以及谁患有原发性感染和重新激活性感染 感染。我们和其他人记录了多个地区的多雨潮湿月份病例增加了 30-70% 国家。我们的流行病学研究表明，这种显着的季节性是由于急性暴露导致 急性原发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，患有急性肺综合征的患者病程较短 和迅速进展的死亡。我们的中心假设是，急性肺部感染的发病率更高。 比重新激活的形式具有更强的致病机制，并且宿主 IgM 和 IgG 模式可以区分这些 形式。我们提出两个相关但独立的目标来检验这一假设。 目的 1. 验证新型抗 Mp1p IgM 和 IgG 酶联免疫分析 (EIA) 并描述 急性原发感染对患者预后的影响。在这里，我们将利用 IVAP 试验生物样本库 来自 440 名经培养确认的纵向血浆样本（24 周内收集的 6 个时间点） 踝部真菌病患者绘制人类 IgM 和 IgG 反应图谱，识别 IgM/IgG 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. 开发一种新型小鼠肺部模型来破译宿主抗 Tm 抗体对 原发感染与再激活感染。在这里，我们将使用非侵入性技术开发一种新型肺部模型 口咽抽吸和低感染接种物模仿自然人类感染。我们将开发一种敏锐的 在 CD4 缺失的小鼠中建立原发感染模型，并在免疫功能正常的小鼠中形成慢性感染，随后 通过 CD4 耗竭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 原发感染与再激活感染之间的反应应有所不同，并使用小鼠抗体数据来确定 加强对人类抗体反应的解释。 影响。我们的研究旨在建立踝部真菌病的血清学诊断，这有可能 区分急性感染和再激活感染并扩大我们对疾病谱的了解。新的小鼠 肺部模型将促进宿主对 Tm 感染免疫反应的新研究。抗体测试 将使基于人群的血清流行率研究能够增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 个人层面和人口层面的预防策略。