B cell subsets and immunity to cryptococcosis

描述(申请人提供)：目前，艾滋病毒相关隐球菌病(隐球菌病，CD)唯一已知的风险因素是CD4T细胞的严重丧失，但这不能区分将发展为CD的艾滋病毒感染者(HIV+)和不会发展为CD的患者。在未感染HIV的患者中，CD没有生物标志物。我们的团队发现，有CD病史或后来发展为CD的HIV+个体的IgM记忆B细胞水平低于从未患有CD的人，而且降低的水平是CD状态的一个强有力的独立预测因素。IGM Memory B细胞，已知在HIV中被耗尽，产生天然的IgM(NIGM)，结合保守的微生物决定簇，并提供现成的病原体防御。因此，IgM记忆B细胞对新生隐球菌(CN)具有保护作用。我们实验室的研究表明，缺乏血清IgM的小鼠(分泌型，SIGM-/-小鼠)在肺部感染CN后的存活率低于IgM充足的小鼠，这与CN的肺泡巨噬细胞吞噬能力降低有关，而过继转移NA血清IgM会增加CN的吞噬能力。虽然关于获得性抗体(即被动或主动免疫)对CN的保护作用已知很多，但B细胞在CD天然抵抗中的作用仍是一个谜。这项应用建议确定NIGM及其来源的B细胞是否对CN具有中介保护作用。我们建议在小鼠中进行研究，以确定小鼠IgM记忆B细胞、B-1B细胞及其产物NIGM的同源物在CN免疫中的作用，以及控制其活性的机制，并进行人类研究，以确定IgM记忆B细胞的表达是否适合CD的生物标志物，并寻找CD相关基因。本研究的目的如下：1)确定B-1B细胞在小鼠抵抗CN中的作用；2)确定B-1B细胞和/或NIGM增强对CN免疫的机制；3)将IgM Memory B细胞的表达与人类CD联系起来，并寻找CN相关的分子图谱。这些目标将对临床医学产生影响，使生物标记物的发现克服早期诊断的障碍，开发新的疫苗和治疗方法以克服有效预防和治疗的障碍，并通过揭示CN-宿主相互作用的新机制来影响基础科学。 公共卫生相关性：隐球菌病是由真菌病原体新生隐球菌(和其他隐球菌种)引起的，是艾滋病毒感染的一种危及生命的并发症，每年在全球主要在撒哈拉以南非洲和东南亚造成90万例和60万人死亡。艾滋病毒相关隐球菌病的破坏性更大，因为艾滋病毒感染者几乎不可能治愈。隐球菌病也发生在接受实体器官移植的患者和看似正常的人身上。目前，没有办法确定哪些艾滋病毒/艾滋病患者会感染隐球菌病，也没有已知的风险因素存在于未感染艾滋病毒/艾滋病或接受过移植手术的人群中。我们实验室的一项研究发现，某些B细胞亚群、IgM记忆B细胞的丢失与HIV相关的隐球菌病之间存在先前未被怀疑的关联。IGM Memory B细胞在HIV感染中耗尽。这项应用的目标是使用小鼠模型来确定(小鼠同源的)IgM记忆B细胞可能增强对隐球菌的保护的机制，并进行人体研究，以确定失去IgM记忆B细胞是否为隐球菌病的风险因素。这项工作的公共卫生意义 是高的。它有可能确定隐球菌疾病的生物标记物，并为开发新的疫苗和疗法提供信息，这是非常需要的，特别是在疾病负担令人震惊的发展中国家。。

DESCRIPTION (provided by applicant): Currently, the only known risk factor for HIV-associated cryptococcal disease (cryptococcosis, CD) is profound loss of CD4T cells, but this cannot discriminate HIV-infected (HIV+) patients who will develop CD from those who will not. There are no biomarkers for CD in HIV-uninfected patients. Our group discovered that HIV+ individuals with a history of or who later developed CD had lower levels of IgM memory B cells than those who never had CD and that a reduced level was a strong independent predictor of CD status. IgM memory B cells, known to be depleted in HIV, produce natural IgM (nIgM) that binds conserved microbial determinants and provides ready-made pathogen defense. Thus, IgM memory B cells could protect against Cryptococcus neoformans (CN). Support for this concept comes from studies from our laboratory demonstrating that mice which lack serum IgM (secretory, sIgM-/- mice) exhibited reduced survival after pulmonary infection with CN than IgM sufficient mice, which was associated with reduced alveolar macrophage phagocytosis of CN that increased with adoptive transfer of na¿ve serum IgM. Although much is known about acquired antibody (i.e. from passive or active immunization) protection against CN, the role of B cells in natural resistance to CD is an enigma. This application proposes to determine whether nIgM and the B cells from which it is derived mediate protection against CN. We propose studies in mice to determine the role of mouse homologs of IgM memory B cells, B-1 B cells, and their product nIgM, in immunity to CN, the mechanisms that govern their activity, and human studies to determine whether IgM memory B cell expression is a suitable biomarker for CD and seek CD-associated genes. The following aims are proposed: 1) To determine the role of B-1 B cells in protection against CN in mice; 2) To identify mechanisms by which B-1 B cells and/or nIgM potentiate immunity to CN; 3) To link IgM memory B cell expression to human CD and seek CN-associated molecular profiles. These aims will have an impact on clinical medicine, informing biomarker discovery to overcome barriers to early diagnosis, development of new vaccines and therapies to overcome barriers to effective prevention and treatment, and impact basic science by revealing novel mechanisms of CN-host interaction. PUBLIC HEALTH RELEVANCE: Cryptococcosis, which is caused by the fungal pathogen, Cryptococcus neoformans (and other Cryptococcus species), is a life-threatening complication of HIV infection, causing > 900,000 cases and > 600,000 deaths annually globally, principally in sub-Saharan Africa and South-east Asia. The devastation of HIV-associated cryptococcosis is even greater because it is nearly impossible to cure in people with HIV infection. Cryptocococcosis also occurs in patients with solid organ transplants and in seemingly normal people. At present, there is no way to identify patients with HIV/AIDS who will get cryptococcosi and there are no known risk factors in people without HIV/AIDS or who have transplants. A study from our laboratory uncovered a previously unsuspected association between the loss of a certain subset of B cells, IgM memory B cells, and HIV-associated cryptococcosis. IgM memory B cells are depleted in HIV infection. The goal of this application is to use mouse models to identify mechanisms by which (the mouse homolog of) IgM memory B cells might potentiate protection against Cryptococcus and to perform human studies to determine if loss of IgM memory B cells is a risk factor for cryptococcosis. The public health significance of this work is high. It has the potential to identify biomarkers of cryptococcal disease and inform the development of new vaccines and therapies, which are greatly needed, especially in the developing world where the burden of disease is staggering. .