Echinocandin treatment of pneumocystis pneumonia in rodent models depletes cysts leaving trophic burdens that cannot transmit the infection.
Echinocandin treatment of pneumocystis pneumonia in rodent models depletes cysts leaving trophic burdens that cannot transmit the infection.
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DOI：
10.1371/journal.pone.0008524
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发表时间：
2010-01-29
期刊：
影响因子：
3.7
通讯作者：
Walzer PD
中科院分区：
文献类型：
--
作者：
Cushion MT;Linke MJ;Ashbaugh A;Sesterhenn T;Collins MS;Lynch K;Brubaker R;Walzer PD
肺孢子虫属真菌在免疫系统衰弱的宿主中引起肺炎（PCP），并作为与慢性疾病（如COPD）相关的共病因素出现。有限的治疗选择和对生命周期的了解不足是这些真菌无法在哺乳动物肺外生长的结果。在肺泡腔内，肺孢子虫属，似乎有一个双相的生命周期，包括以营养型二分裂为特征的无性阶段和导致形成包囊的有性周期，但传播感染的生命周期阶段尚不清楚。孢囊表达β-1，3-D-葡聚糖合成酶，并含有丰富的β-1，3-D-葡聚糖，而营养型孢囊不表达。在此，我们发现，棘白菌素（一种抑制β-1，3-D-葡聚糖合成的化合物）对PCP进行治疗性和预防性处理后，PCP啮齿动物模型中的包囊减少，同时保留了大量的营养型。棘白菌素处理的小鼠的存活率提高，可能是由于处理的小鼠和大鼠肺中β-1，3-D-葡聚糖含量降低，这与囊肿数量减少和有机体形态的显著重塑一致。阿尼芬净治疗的小鼠未能传播感染，这为囊肿作为传播媒介提供了强有力的证据。我们第一次发现停止阿尼芬净治疗并继续免疫抑制可以使囊肿重新形成。单用棘白菌素治疗PCP不太可能根除感染，停止棘白菌素治疗而患者仍处于免疫抑制状态可能导致复发。重要的是，棘白菌素提供了新的和强大的化学工具，以探测仍然知之甚少的这种真菌病原体的双相生命周期。
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 β -1,3-D-glucan synthetase and contain abundant β -1,3-D-glucan. Here we show that therapeutic and prophylactic treatment of PCP with echinocandins, compounds which inhibit the synthesis of β -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 β -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.
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影响因子：
--
作者：
Icenhour, CR;Rebholz, SL;Cushion, MT
通讯作者：
Cushion, MT
影响因子：
11.8
作者：
Linke MJ;Rebholz S;Collins M;Tanaka R;Cushion MT
通讯作者：
Cushion MT
影响因子：
4.9
作者：
Cushion, Melanie T.;Walzer, Peter D.;Huang, Tien L.
通讯作者：
Huang, Tien L.
DOI：
10.1165/rcmb.2004-0300oc
发表时间：
2005-06-01
影响因子：
6.4
作者：
Evans, SE;Hahn, PY;Limper, AH
通讯作者：
Limper, AH
影响因子：
1
作者：
Beltz, K.;Kramm, C. M.;Goebel, U.
通讯作者：
Goebel, U.