College of Medicine, University of Cincinnati, Cincinnati, Ohio, United States of America.
PLoS One. 2010 Jan 29;5(1):e8524. doi: 10.1371/journal.pone.0008524.
Fungi in the genus Pneumocystis cause pneumonia (PCP) in hosts with debilitated immune systems and are emerging as co-morbidity factors associated with chronic diseases such as COPD. Limited therapeutic choices and poor understanding of the life cycle are a result of the inability of these fungi to grow outside the mammalian lung. Within the alveolar lumen, Pneumocystis spp., appear to have a bi-phasic life cycle consisting of an asexual phase characterized by binary fission of trophic forms and a sexual cycle resulting in formation of cysts, but the life cycle stage that transmits the infection is not known. The cysts, but not the trophic forms, express beta -1,3-D-glucan synthetase and contain abundant beta -1,3-D-glucan. Here we show that therapeutic and prophylactic treatment of PCP with echinocandins, compounds which inhibit the synthesis of beta -1,3-D-glucan, depleted cysts in rodent models of PCP, while sparing the trophic forms which remained in significant numbers. Survival was enhanced in the echincandin treated mice, likely due to the decreased beta -1,3-D-glucan content in the lungs of treated mice and rats which coincided with reductions of cyst numbers, and dramatic remodeling of organism morphology. Strong evidence for the cyst as the agent of transmission was provided by the failure of anidulafungin-treated mice to transmit the infection. We show for the first time that withdrawal of anidulafungin treatment with continued immunosuppression permitted the repopulation of cyst forms. Treatment of PCP with an echinocandin alone will not likely result in eradication of infection and cessation of echinocandin treatment while the patient remains immunosuppressed could result in relapse. Importantly, the echinocandins provide novel and powerful chemical tools to probe the still poorly understood bi-phasic life cycle of this genus of fungal pathogens.
肺囊虫属真菌可引起免疫系统受损宿主的肺炎（PCP），并成为与 COPD 等慢性疾病相关的合并症因素。由于这些真菌无法在哺乳动物肺外生长，因此治疗选择有限，生命周期理解不足。在肺泡腔内，肺囊虫属似乎具有双相生命周期，包括以营养形式的二分裂为特征的无性阶段和导致形成囊肿的有性周期，但传播感染的生命周期阶段尚不清楚。囊肿，但不是营养形式，表达β-1,3-D-葡聚糖合酶并含有丰富的β-1,3-D-葡聚糖。在这里，我们表明，用棘白菌素治疗和预防 PCP，可抑制β-1,3-D-葡聚糖的合成，可使啮齿动物 PCP 模型中的囊肿枯竭，而营养形式则大量保留。在接受棘白菌素治疗的小鼠中，生存率得到提高，这可能是由于治疗小鼠和大鼠肺部的β-1,3-D-葡聚糖含量降低，与囊肿数量减少以及生物体形态的剧烈重塑相一致。棘白菌素治疗未能使感染传播，为囊肿作为传播剂提供了有力证据。我们首次表明，在继续免疫抑制的情况下停止棘白菌素治疗可允许囊肿形式重新出现。单独使用棘白菌素治疗 PCP 不太可能导致感染根除，而在患者仍然免疫抑制的情况下停止棘白菌素治疗可能导致复发。重要的是，棘白菌素为研究这一真菌病原体属的仍然了解甚少的双相生命周期提供了新颖而强大的化学工具。
