Meiosis in cryptococcal infection

隐球菌感染中的减数分裂

• 批准号: 9355796
• 负责人: Xiaorong Lin
• 金额: --
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-08 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9355796
• 关键词: Acquired Immunodeficiency Syndrome; Animals; Behavior monitoring; Breathing; Cell Size; Cells; Cessation of life; Couples; Cryptococcus; Cryptococcus neoformans; Cryptococcus neoformans infection; DNA; Data; Development; Diploidy; Disease Progression; Drug resistance; Environment; Epidemiology; Formulation; Frequencies; Gametogenesis; General Population; Genes; Genetic Recombination; Genotoxic Stress; Goals; Grant; HIV Infections; Haploid Cells; Haploidy; High Prevalence; Histones; Human; Image; Immunity; Immunocompetent; Immunocompromised Host; Impairment; In Vitro; Individual; Infection; Investigation; Kinetics; Knowledge; Life Cycle Stages; Lung; Malignant Neoplasms; Meiosis; Meiotic Recombination; Mus; Mutation; Nuclear; Outcome; Pathogenesis; Patients; Phenotype; Ploidies; Polyploid Cells; Polyploidy; Population; Process; Proteins; Public Health; Radiation therapy; Reproduction; Research; Serum; Sister Chromatid; Synaptonemal Complex; Systemic disease; Systemic infection; Technology; Testing; Therapeutic immunosuppression; Time; Tissues; Work; base; cancer cell; chemotherapy; cohesion; fungus; genotoxicity; in vivo; irradiation; latent infection; mouse model; mutant; neoplastic cell; pandemic disease; pathogen; permissiveness; population based; reactivation from latency; recombinase; response; sexual role; spindle pole body

ABSTRACT The fungal pathogen Cryptococcus neoformans is responsible for more than half a million deaths worldwide each year largely because of the AIDS pandemic. Epidemiological evidence indicates a high prevalence of non-symptomatic cryptococcal infections in the general population. Fatal systemic diseases often occur through re-activation of latent infections in patients when their immunity is impaired by HIV infection or immunosuppressive therapies. Although Cryptococcus typically grows in a haploid state, large polyploid Cryptococcus cells (mostly 4C and occasionally 8C) are observed in infected lungs and are proposed to promote cryptococcal latency and persistence. These polyploid cells can subsequently give rise to small haploid cryptococcal populations. It is unclear how ploidy reduction occurs in Cryptococcus during infection and whether this process contributes to Cryptococcus reactivation. Our preliminary data indicate that a subpopulation of Cryptococcus cells become large in serum with meiosis mutants showing increased proportion of cells with elevated cell size. Interestingly, we found that large polyploid cryptococcal cells induced by genotoxic stress showed meiosis-like features during de- polyploidization process in vitro. Consistently, blocking meiosis impedes ploidy reduction in vitro. The meiosis mutants also showed reduced fungal burden in the lungs compared to the wild type when polyploid cells were used to inoculate mice. Most excitingly, we found that the meiosis-specific recombinase gene DMC1 is activated in Cryptococcus during infection in the murine model of cryptococcosis. These preliminary data led us to hypothesize that Cryptococcus can respond to the hostile host environment by polyploidization and this fungus can return to normal ploidy through meiosis in a permissive host condition due to HIV infection, generating proliferative haploid progeny and causing fatal systemic infections. Thus the life-cycle associated progression of cryptococcosis might be similar to the gametogenesis process of cancer. In that process, various cancer cells become polyploid in response to genotoxic chemotherapy or radiation therapy. These polyploid tumor cells can de-polyploidize through a meiosis-like process, giving rise to rejuvenated and proliferative cancer cells with normal ploidy. In this exploratory R21 proposal, our objectives are to determine the occurrence of meiosis in Cryptococcus during infection (Aim 1), and to dissect the process of ploidy reduction in this pathogen and to assess the contribution of meiosis to cryptococcal pathogenesis (Aim 2). The proposed work is a stepping stone for further comprehensive investigation into the important and yet poorly understood aspects of cryptococcal disease progression (latency and reactivation).

抽象的 真菌病原体Neoformans造成超过500万人死亡 全世界每年都大多是由于艾滋病大流行。流行病学证据表明很高 普通人群中非症状的隐球菌感染的患病率。致命的系统性疾病 通常，当患者的免疫力受到HIV感染损害时，通常通过重新激活潜在感染而发生 或免疫抑制疗法。尽管隐球菌通常在单倍体状态下生长，但多倍多倍体 在感染的肺中观察到隐孢子菌细胞（主要是4C，有时是8C），并提出为 促进隐球菌潜伏期和持久性。这些多倍体细胞随后会产生小 单倍体隐球菌种群。目前尚不清楚感染过程中的加密赛中如何发生倍数减少 以及该过程是否有助于加密环球重新激活。 我们的初步数据表明，在血清中，加密球菌的亚群变得很大 减数分裂突变体显示细胞大小升高的细胞比例增加。有趣的是，我们发现很大 通过遗传毒性应激诱导的多倍体加密局会在降低期间表现出细量的特征 多倍体化过程体外。一致地，阻塞减数分裂会导致体外倍增。减数分裂 与野生型相比，当多倍体细胞为 用于接种小鼠。最令人兴奋的是，我们发现减数分裂特异性重组酶基因DMC1是 在感染过程中，在隐球菌病鼠模型中被激活。这些初步数据LED 我们假设加密球可以通过多倍体化对敌对的宿主环境做出反应，这 由于HIV感染，真菌可以通过减数分裂通过减数分裂恢复正常的倍性， 产生增殖的单倍体后代并引起致命的全身感染。因此，生命周期相关 隐球菌病的进展可能类似于癌症的配子发生过程。在此过程中， 各种癌细胞响应于遗传毒性化疗或放射治疗而变成多倍体。这些 多倍体肿瘤细胞可以通过减数分裂样过程去除多酶，从而引起恢复活力和 具有正常倍性的增生性癌细胞。在此探索性R21提案中，我们的目标是确定 感染过程中加密赛中减数分裂的发生（AIM 1），并剖析倍性的过程 减少这种病原体并评估减数分裂对隐球菌发病机理的贡献（AIM 2）。这 拟议的工作是一块垫脚石，用于对重要但差的进一步全面调查 理解了隐球菌疾病进展的方面（潜伏期和重新激活）。