Comparison of pathogenesis and host immune responses to Candida glabrata and Candida albicans in systemically infected immunocompetent mice
Comparison of pathogenesis and host immune responses to Candida glabrata and Candida albicans in systemically infected immunocompetent mice
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DOI：
10.1128/iai.69.8.5046-5055.2001
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发表时间：
2001-08-01
影响因子：
3.1
通讯作者：
Hare, R
中科院分区：
文献类型：
--
作者：
Brieland, J;Essig, D;Hare, R
细胞因子介导的宿主对光滑念珠菌感染的防御与对C.白色念珠菌，使用免疫活性的小鼠系统性念珠菌病模型。感染的发病机制进行了评估形态学和培养的靶器官，而在肾脏中的细胞因子mRNA和相应的蛋白质的诱导动力学进行了测定，分别通过实时逆转录-PCR和精氨酸特异性鼠酶联免疫吸附试验。全身感染C. glabrata引起慢性非致死性感染，并从肾脏中恢复微生物，而静脉接种C.白色念珠菌导致快速死亡，肾脏中的微生物呈对数生长，念珠菌恢复。脾脏肝脏和肺部的白色念珠菌C的生存。glabrata感染的小鼠与促炎细胞因子肿瘤坏死因子α（TNF-α）、白细胞介素-12（IL-12）和γ干扰素（IFN-γ）的mRNA和相应免疫反应性蛋白的快速诱导以及抗炎细胞因子IL-10的蛋白诱导缺乏相关。相反，C.白色念珠菌感染的小鼠与IL-10的mRNA和相应蛋白的诱导有关，但延迟（即，TNF-α）或不存在（即，IL-12和IFN-γ）诱导免疫反应性促炎细胞因子。随后用针对TNF-α、IL-12或IFN-γ的精氨酸特异性中和单克隆抗体（MAb）处理小鼠，并观察对C.评估肾脏中的光滑度。内源性TNF-α的中和导致C. glabrata微生物相比，同样感染的小鼠给予同种型匹配的对照单克隆抗体，而内源性IL-12或IFN-γ的中和对C.光滑复制这些结果表明，静脉接种C. glabrata，免疫活性小鼠发生慢性非致命性肾脏感染，其与促炎细胞因子TNF-α、IL-12和IFN-γ的快速诱导相关。此外，TNF-α在宿主防御由C. glabrata或C.白色念珠菌，因为内源性TNF-α活性的缺乏与两种感染模型中组织负荷的增加有关。
Cytokine-mediated host defense against Candida glabrata infection was compared to that against C. albicans, using immunocompetent murine models of systemic candidiasis. The pathogenesis of infection was evaluated morphologically and by culture of target organs, while the kinetics of induction of cytokine mRNAs and corresponding proteins were determined in kidneys by real-time reverse transcription-PCR and cytokine-specific murine enzyme-linked immunosorbent assays, respectively. Systemic infection with C. glabrata resulted in a chronic, nonfatal infection with recovery of organisms from kidneys, while intravenous inoculation with C. albicans resulted in rapid mortality with logarithmic growth of organisms in kidneys and recovery of C. albicans from the spleen, liver, and lungs. Survival of C. glabrata-infected mice was associated with rapid induction of mRNAs and corresponding immunoreactive proteins for the proinflammatory cytokines tumor necrosis factor alpha (TNF-alpha), interleukin-12 (IL-12), and gamma interferon (IFN-gamma) and the lack of induction of protein for the anti-inflammatory cytokine IL-10. In contrast, mortality in C. albicans-infected mice was associated with induction of mRNA and corresponding protein for IL-10 but delayed (i.e., TNF-alpha) or absent (i.e., IL-12 and IFN-gamma) induction of immunoreactive proinflammatory cytokines. Mice were subsequently treated with cytokine-specific neutralizing monoclonal antibodies (MAbs) to TNF-alpha, IL-12, or IFN-gamma, and the effect on growth of C. glabrata in kidneys was assessed. Neutralization of endogenous TNF-alpha resulted in a significant increase in C. glabrata organisms compared to similarly infected mice administered an isotype-matched control MAb, while neutralization of endogenous IL-12 or IFN-gamma had no significant effect on C. glabrata replication. These results demonstrate that in response to intravenous inoculation of C. glabrata, immunocompetent mice develop chronic nonfatal renal infections which are associated with rapid induction of the proinflammatory cytokines TNF-alpha, IL-12, and IFN-gamma. Furthermore, TNF-alpha plays a key role in host defense against systemic candidiasis caused by either C. glabrata or C. albicans, as the absence of endogenous TNF-alpha activity was associated with enhanced tissue burden in both infection models.