Toll-like receptor modulation of murine cerebral malaria is dependent on the genetic background of the host
Toll-like receptor modulation of murine cerebral malaria is dependent on the genetic background of the host
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DOI：
10.1086/522865
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发表时间：
2007-11-15
影响因子：
6.4
通讯作者：
Bucala, Richard
中科院分区：
文献类型：
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作者：
Griffith, Jason W.;O'Connor, Christine;Bucala, Richard
伯氏疟原虫ANKA感染是人脑型疟疾（CM）的一种成熟模型。我们在此表明Toll样受体（TLR）信号传导影响伯氏疟原虫ANKA感染小鼠中致死CM的发展。结果的调节依赖于遗传背景，例如在易感的C57 BL/ 6背景上缺失髓样分化因子（MyD）88导致对CM的抗性，而在抗性的BALB/ c背景上缺失MyD 88导致死亡率增加。我们的数据表明，MyD 88影响T辅助极化细胞因子的产生，包括干扰素（IFN）-γ，白细胞介素（IL）-4，IL-17，以及Foxp 3（+）调节性T（T-reg）细胞的总数，其方式取决于宿主的遗传背景。此外，IFN-γ、CXCL 10和CXCL 9的mRNA水平在易感野生型而非MyD 88（-/-）感染小鼠的脑中强烈上调。这些结果表明TLR信号传导和宿主遗传背景通过调节细胞因子产生和Treg细胞数量影响CM的发病机制。
Infection with Plasmodium berghei ANKA is a well-established model of human cerebral malaria (CM). We show herein that Toll-like receptor (TLR) signaling influences the development of lethal CM in P. berghei ANKA infected mice. Modulation of outcome was dependent on genetic background, such that deletion of myeloid differentiation factor (MyD) 88 on the susceptible C57BL/ 6 background resulted in resistance to CM, whereas deletion of MyD88 on the resistant BALB/ c background led to increased mortality. Our data show that MyD88 influenced the production of T helper-polarizing cytokines, including interferon (IFN)-gamma, interleukin (IL)-4, and IL-17, as well as the total number of Foxp3(+) regulatory T (T-reg) cells in a manner dependent on host genetic background. In addition, mRNA levels of IFN-gamma, CXCL10, and CXCL9 were strongly up-regulated in the brains of susceptible wild-type but not MyD88(-/-) infected mice. These results suggest that TLR signaling and host genetic background influences the pathogenesis of CM via modulation of cytokine production and Treg cell numbers.