Mapping of the IgM and IgG antibody responses to Talaromyces marneffei infection in mice and humans - Deciphering acute from reactivated or latent infections

摘要 Talaromycosis是一种侵袭性真菌病，由马尔尼菲Talaromycesmarneffei（Tm）引起， 东南亚感染导致三分之一的免疫系统受损的感染者死亡， 艾滋病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 感染晚期。我们知道感染可以在返回的旅行者中重新激活长达7年的暴露， 我们缺乏抗体测试来确定谁已经感染，谁有一个主要的与重新激活 感染我们和其他人记录了在多雨潮湿的月份， 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暴露导致的， 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 临床试验表明，急性肺综合征患者的病程较短， 并迅速增加死亡率我们的中心假设是，急性肺部感染的形式有更多的 毒力致病比再活化形式，和宿主IgM和IgG模式可以区分这些 forms.我们提出了两个相关但独立的目标来检验这一假设。 AIM 1.验证新的抗Mp 1 p IgM和IgG酶免疫测定法（EIA），并描述 急性原发性感染对患者预后的影响。在这里，我们将利用IVAP试验生物储存库 纵向血浆样本（24周内收集的6个时间点），来自440例经培养证实的 在人类中绘制IgM和IgG反应，确定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结局的影响。 AIM 2.开发一种新的小鼠肺模型，以破译宿主抗Tm抗体对 原发感染与再激活感染。在这里，我们将开发一种新的肺模型， 口咽抽吸和低感染接种物以模拟自然人类感染。我们会发展出一种急性的 在CD 4耗竭小鼠中建立原发性感染模型，并在免疫活性小鼠中发展慢性感染， 通过CD 4耗竭诱导再活化感染模型。我们的目标是了解哺乳动物的抗体 初次感染与再激活感染之间的反应应该不同，并使用小鼠抗体数据 加强对人类抗体反应的解释。 冲击我们的研究旨在建立一种有潜力的踝菌病的血清学诊断方法， 区分急性和再活化感染，扩大我们对疾病谱的认识。新鼠 肺模型将促进对Tm感染的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。这些知识将为疾病管理提供信息， 在个人层面和人口层面的预防战略。

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.