Impairment of Host Defense against Disseminated Candidiasis in Mice Overexpressing GATA-3
Impairment of Host Defense against Disseminated Candidiasis in Mice Overexpressing GATA-3
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DOI：
10.1128/iai.01398-09
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发表时间：
2010-05-01
影响因子：
3.1
通讯作者：
Hizawa, Nobuyuki
中科院分区：
文献类型：
--
作者：
Haraguchi, Norihiro;Ishii, Yukio;Hizawa, Nobuyuki
念珠菌是院内侵袭性真菌感染最常见的来源。先前的研究表明，辅助性t免疫反应是念珠菌感染易感性的关键宿主因素。转录因子GATA-3被认为是辅助t型2 （Th2）分化的主要调控因子。因此，我们利用过表达GATA-3的转基因小鼠研究了GATA-3在宿主防御系统性念珠菌感染中的作用。gata -3过表达小鼠感染念珠菌后的存活率明显低于野生型小鼠。与野生型小鼠相比，gata -3过表达小鼠肾脏中念珠菌的生长明显增加。假丝酵母感染后，gata -3过表达小鼠脾细胞中白细胞介素-4 （IL-4）、IL-5、IL-13等多种Th2细胞因子水平显著升高，Th1细胞因子γ干扰素水平显著降低。gata -3过表达小鼠对念珠菌感染的腹腔巨噬细胞募集和吞噬活性明显低于野生型小鼠。外源性γ干扰素给过表达gata -3的小鼠显著减少了假丝酵母在肾脏中的生长，从而提高了存活率。γ干扰素的管理也增加巨噬细胞募集到腹腔，以应对念珠菌感染。这些结果表明，GATA-3的过表达调节巨噬细胞的抗真菌活性，从而增强对全身念珠菌感染的易感性，可能是通过减少对念珠菌感染的反应中γ干扰素的产生来实现的。
Candida species are the most common source of nosocomial invasive fungal infections. Previous studies have indicated that T-helper immune response is the critical host factor for susceptibility to Candida infection. The transcription factor GATA-3 is known as the master regulator for T-helper type 2 (Th2) differentiation. We therefore investigated the role of GATA-3 in the host defense against systemic Candida infection using GATA-3-overexpressing transgenic mice. The survival of GATA-3-overexpressing mice after Candida infection was significantly lower than that of wild-type mice. Candida outgrowth was significantly increased in the kidneys of GATA-3-overexpressing mice, compared with wild-type mice. The levels of various Th2 cytokines, including interleukin-4 (IL-4), IL-5, and IL-13, were significantly higher while the level of Th1 cytokine gamma interferon was significantly lower in the splenocytes of GATA-3-overexpressing mice after Candida infection. Recruitment of macrophages into the peritoneal cavity in response to Candida infection and their phagocytic activity were significantly lower in GATA-3-overexpressing mice than in wild-type mice. Exogenous administration of gamma interferon to GATA-3-overexpressing mice significantly reduced Candida outgrowth in the kidney and thus increased the survival rate. Administration of gamma interferon also increased the recruitment of macrophages into the peritoneal cavity in response to Candida infection. These results indicate that overexpression of GATA-3 modulates macrophage antifungal activity and thus enhances the susceptibility to systemic Candida infection, possibly by reducing the production of gamma interferon in response to Candida infection.