Meiosis In Cryptococcal Infection

隐球菌感染中的减数分裂

• 批准号: 9530730
• 负责人: Xiaorong Lin
• 金额: $ 23.93万
• 依托单位: UNIVERSITY OF GEORGIA
• 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 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9530730
• 关键词: Meiosis; Cryptococcal; Infection

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).

摘要 真菌病原体新型隐球菌造成50多万人死亡 每年全球范围内，主要是因为艾滋病的流行。流行病学证据表明， 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，通常通过潜伏感染的重新激活而发生 或免疫抑制疗法。虽然隐球菌通常以单倍体状态生长，但大的多倍体 在感染的肺中观察到隐球菌细胞（大多数为4C，偶尔为8C）， 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 单倍隐球菌种群。目前还不清楚隐球菌在感染过程中是如何发生倍性减少的 以及这一过程是否有助于隐球菌的重新激活。 我们的初步数据表明，隐球菌细胞的一个亚群在血清中变大， 减数分裂突变体显示细胞比例增加，细胞尺寸增大。有趣的是，我们发现， 由遗传毒性应激诱导的多倍体隐球菌细胞在去分化过程中表现出减数分裂样特征， 多倍体化过程。因此，在体外阻断减数分裂会阻碍倍性降低。减数分裂 与野生型相比，突变体还显示出当多倍体细胞被接种时肺中真菌负荷减少。 用来喂老鼠的最令人兴奋的是，我们发现减数分裂特异性重组酶基因DMC 1是 在隐球菌病的鼠模型中感染期间在隐球菌中激活。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， 真菌可以在由于HIV感染而允许的宿主条件下通过减数分裂恢复到正常的倍性， 产生增殖性单倍体后代并引起致命的全身性感染。因此， 隐球菌病的进展可能类似于癌症的配子发生过程。在这个过程中， 各种癌细胞响应于遗传毒性化学疗法或放射疗法而变成多倍体。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体化，从而产生再生的肿瘤细胞， 具有正常倍性的增殖性癌细胞。在这个探索性的R21提案中，我们的目标是确定 隐球菌在感染过程中减数分裂的发生（目的1），并剖析倍性过程 减少这种病原体，并评估减数分裂对隐球菌发病机制的贡献（目的2）。的 拟议的工作是进一步全面调查重要但很差的 了解隐球菌疾病进展的各个方面（潜伏期和再激活）。