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 真菌病原体新型隐球菌导致超过 50 万人死亡 每年在世界范围内流行主要是由于艾滋病的流行。流行病学证据表明高 一般人群中无症状隐球菌感染的患病率。致命的全身性疾病 当患者的免疫力因 HIV 感染而受损时，通常会通过重新激活患者的潜伏感染而发生 或免疫抑制疗法。尽管隐球菌通常以单倍体状态生长，但大的多倍体 在受感染的肺部中观察到隐球菌细胞（主要为 4C，偶尔为 8C），建议 促进隐球菌潜伏期和持久性。这些多倍体细胞随后可以产生小的 单倍体隐球菌群体。目前尚不清楚隐球菌在感染过程中如何发生倍性减少 以及这个过程是否有助于隐球菌的重新激活。 我们的初步数据表明，血清中的隐球菌细胞亚群随着时间的推移而变大 减数分裂突变体显示细胞比例增加且细胞尺寸增大。有趣的是，我们发现大 基因毒性应激诱导的多倍体隐球菌细胞在脱细胞过程中表现出减数分裂样特征 体外多倍化过程。一致地，阻断减数分裂会阻碍体外倍性减少。减数分裂 当多倍体细胞被处理时，与野生型相比，突变体还显示出肺部真菌负担减少。 用于给小鼠接种。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 在隐球菌病小鼠模型感染过程中，隐球菌被激活。这些初步数据导致 我们假设隐球菌可以通过多倍化来应对恶劣的宿主环境，这 由于艾滋病毒感染，真菌可以在允许的宿主条件下通过减数分裂恢复正常倍性， 产生增殖性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与癌症的配子发生过程相似。在那个过程中， 各种癌细胞响应基因毒性化疗或放疗而变成多倍体。这些 多倍体肿瘤细胞可以通过类似减数分裂的过程去多倍化，从而产生恢复活力和 具有正常倍性的增殖性癌细胞。在这个探索性 R21 提案中，我们的目标是确定 隐球菌感染过程中减数分裂的发生（目标1），并剖析倍性过程 减少该病原体并评估减数分裂对隐球菌发病机制的贡献（目标 2）。这 拟议的工作是进一步全面调查重要但不充分的问题的垫脚石 了解隐球菌疾病进展的各个方面（潜伏期和重新激活）。