B cell subsets and immunity to cryptococcosis

B 细胞亚群和隐球菌病免疫

基本信息

批准号：
9031052
负责人：
Liise-anne Pirofski
金额：
$ 54.83万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9031052
关键词：
AIDS/HIV problem Active Immunization Address Adoptive Transfer Africa South of the Sahara Alveolar Macrophages Anti-Retroviral Agents Antibodies Antifungal Agents Antigens B-Lymphocyte Subsets B-Lymphocytes Basic Science Binding Biological Markers Blood Brain CD4 Positive T Lymphocytes Carbohydrates Cells Cessation of life Clinical Medicine Clinical Sciences Complication Containment Cryptococcus Cryptococcus neoformans Cryptococcus neoformans infection Development Diagnosis Disease Disease Outbreaks Early Diagnosis Effector Cell Encapsulated Exhibits Far East Gene Expression Gene Expression Profile Genes Goals HIV HIV Infections Homologous Gene Human Human Activities Immunity Immunocompromised Host Immunoglobulin M Immunologic Deficiency Syndromes Immunosuppressive Agents Immunotherapy Individual Infection Inflammation Inflammatory Response Laboratories Life Link Lung Mediating Memory B-Lymphocyte Molecular Profiling Mus Natural Products Natural Resistance Organ Transplantation Pacific Northwest Passive Immunization Pathology Patients Phagocytosis Play Polysaccharides Predisposition Prevention Public Health Recording of previous events Recurrence Resistance Risk Risk Factors Role Serum Solid Source Southeastern Asia Streptococcus pneumoniae Transplant Recipients Transplantation Vaccines Work antigen binding biomarker discovery burden of illness cohort diagnostic biomarker glucuronoxylomannan humoral immunity deficiency interest macrophage microbial mouse model novel novel strategies novel therapeutics novel vaccines pathogen peripheral blood preclinical study prevent profiles in patients secretory IgM

项目摘要

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.

描述（由申请人提供）：目前，HIV 相关隐球菌病（隐球菌病，CD）唯一已知的危险因素是 CD4T 细胞的严重丧失，但这不能区分将发展为 CD 的 HIV 感染者（HIV+）和那些患有 CD 的患者。在未感染 HIV 的患者中，没有 CD 的生物标志物。我们的研究小组发现，有 CD 病史或后来患 CD 的 HIV 阳性患者的 IgM 记忆 B 细胞水平低于从未感染过 CD 的患者。 CD 水平降低是 IgM 记忆 B 细胞（已知在 HIV 中被耗尽）产生天然 IgM (nIgM)，其结合保守的微生物决定簇并提供现成的病原体防御。 B 细胞可以预防新型隐球菌 (CN)，这一观点的支持来自我们实验室的研究，该研究表明缺乏血清 IgM 的小鼠（分泌型，sIgM-/- 小鼠）表现出减少。 CN 肺部感染后的存活率高于 IgM 充足小鼠，这与肺泡巨噬细胞对 CN 的吞噬作用减少有关，而 CN 的吞噬作用随着过继转移而增加。尽管对于获得性抗体（即来自被动或主动免疫）对 CN 的保护作用了解甚多，但 B 细胞在 CD 天然抵抗中的作用仍是一个谜。它是针对 CN 的介导保护作用，我们建议在小鼠中进行研究，以确定 IgM 记忆 B 细胞、B-1 B 细胞及其产物 nIgM 的小鼠同源物在 CN 免疫中的作用。控制其活性的机制，以及 IgM 记忆 B 细胞表达是否是 CD 的合适生物标志物的人体研究，并寻求 CD 相关基因： 1) 确定 B-1 B 细胞在保护中的作用。对抗小鼠 CN；2) 确定 B-1 B 细胞和/或 nIgM 增强 CN 免疫的机制；3) 将 IgM 记忆 B 细胞表达与人类 CD 联系起来，并寻找 CN 相关的分子谱。影响临床医学，为生物标志物发现提供信息以克服早期诊断的障碍，开发新的疫苗和疗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。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Naïve B cells reduce fungal dissemination in Cryptococcus neoformans infected Rag1-/- mice.

幼稚 B 细胞可减少新型隐球菌感染 Rag1-/- 小鼠中的真菌传播。

DOI：
发表时间：
2018-01-01
期刊：
影响因子：
5.2
作者：
Dufaud, Chad;Rivera, Johanna;Rohatgi, Soma;Pirofski, Liise
通讯作者：
Pirofski, Liise

Antibody Responses in HIV-Infected Patients With Advanced Immunosuppression and Asymptomatic Cryptococcal Antigenemia.

患有晚期免疫抑制和无症状隐球菌抗原血症的 HIV 感染患者的抗体反应。

DOI：
发表时间：
2019-01
期刊：
影响因子：
4.2
作者：
Hlupeni, Admire;Nakouzi, Antonio;Wang, Tao;Boyd, Kathryn F;Makadzange, Tariro A;Ndhlovu, Chiratidzo E;Pirofski, Liise
通讯作者：
Pirofski, Liise

Host immunity to Cryptococcus neoformans.

宿主对新型隐球菌的免疫力。

DOI：
10.2217/fmb.14.132
发表时间：
2015
期刊：
Future microbiology
影响因子：
3.1
作者：
Rohatgi S;Pirofski LA
通讯作者：
Pirofski LA

Exserohilum rostratum fungal meningitis associated with methylprednisolone injections.

与甲基强的松龙注射相关的 Exserohilum rostratum 真菌性脑膜炎。

DOI：
发表时间：
2013-02
期刊：
影响因子：
3.1
作者：
Casadevall A;Pirofski LA
通讯作者：
Pirofski LA

Antibody and B Cell Subset Perturbations in Human Immunodeficiency Virus-Uninfected Patients With Cryptococcosis.

未感染人类免疫缺陷病毒的隐球菌病患者的抗体和 B 细胞亚群扰动。

DOI：
发表时间：
2018-01
期刊：
影响因子：
4.2
作者：
Rohatgi, Soma;Nakouzi, Antonio;Carreño, Leandro J;Slosar;Kuniholm, Mark H;Wang, Tao;Pappas, Peter G;Pirofski, Liise
通讯作者：
Pirofski, Liise