Candida glabrata Persistence in Mice Does Not Depend on Host Immunosuppression and Is Unaffected by Fungal Amino Acid Auxotrophy
Candida glabrata Persistence in Mice Does Not Depend on Host Immunosuppression and Is Unaffected by Fungal Amino Acid Auxotrophy
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DOI：
10.1128/iai.01244-09
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发表时间：
2010-03-01
影响因子：
3.1
通讯作者：
Hube, B.
中科院分区：
文献类型：
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作者：
Jacobsen, I. D.;Brunke, S.;Hube, B.
光滑念珠菌已成为人类重要的真菌病原体，在免疫功能低下的患者中引起危及生命的感染。相比之下，即使感染剂量很高，小鼠在受到全身攻击后也不会发病。在这项研究中，我们发现白细胞减少症（而不是皮质类固醇治疗）会导致真菌负荷比免疫功能正常的小鼠暂时增加。然而，即使是免疫能力强的小鼠也无法在 4 周内清除感染。根据临床参数（包括血液酶水平、组织学、髓过氧化物酶和细胞因子水平）监测，组织损伤和对微脓肿的免疫反应轻微。此外，我们研究了氨基酸营养缺陷型光滑念珠菌菌株对于体外和体内适应性和/或毒力研究的适用性。组氨酸、亮氨酸或色氨酸营养缺陷型以及这些营养缺陷型的组合不影响在丰富培养基中的体外生长。在感染第一周期间，免疫功能正常小鼠中所有营养缺陷型菌株的存活率与亲代野生型菌株相似，并且在感染后 4 周仅轻度降低，表明光滑 C. glabrata 在感染期间能够利用广泛的宿主来源的营养物质。这些数据表明光滑 C. glabrata 组氨酸、亮氨酸或色氨酸营养缺陷型菌株适合生成用于体内研究的敲除突变体。值得注意的是，我们的工作表明光滑念珠菌已成功开发出免疫逃避策略，使其能够在哺乳动物宿主体内生存、传播和持续存在。
Candida glabrata has emerged as an important fungal pathogen of humans, causing life-threatening infections in immunocompromised patients. In contrast, mice do not develop disease upon systemic challenge, even with high infection doses. In this study we show that leukopenia, but not treatment with corticosteroids, leads to fungal burdens that are transiently increased over those in immunocompetent mice. However, even immunocompetent mice were not capable of clearing infections within 4 weeks. Tissue damage and immune responses to microabscesses were mild as monitored by clinical parameters, including blood enzyme levels, histology, myeloperoxidase, and cytokine levels. Furthermore, we investigated the suitability of amino acid auxotrophic C. glabrata strains for in vitro and in vivo studies of fitness and/or virulence. Histidine, leucine, or tryptophan auxotrophy, as well as a combination of these auxotrophies, did not influence in vitro growth in rich medium. The survival of all auxotrophic strains in immunocompetent mice was similar to that of the parental wild-type strain during the first week of infection and was only mildly reduced 4 weeks after infection, suggesting that C. glabrata is capable of utilizing a broad range of host-derived nutrients during infection. These data suggest that C. glabrata histidine, leucine, or tryptophan auxotrophic strains are suitable for the generation of knockout mutants for in vivo studies. Notably, our work indicates that C. glabrata has successfully developed immune evasion strategies enabling it to survive, disseminate, and persist within mammalian hosts.