Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, 0049 CARL Building Box 3053, 213 Research Drive, Durham, NC, 27710, USA.
Duke University Program in Genetics and Genomics, Duke University, Durham, NC, 27710, USA.
Sci Rep. 2020 Oct 26;10(1):18269. doi: 10.1038/s41598-020-75129-y.
Susceptibility to infectious diseases is determined by a complex interaction between host and pathogen. For infections with the obligate intracellular bacterium Chlamydia trachomatis, variation in immune activation and disease presentation are regulated by both host genetic diversity and pathogen immune evasion. Previously, we discovered a single nucleotide polymorphism (rs2869462) associated with absolute abundance of CXCL10, a pro-inflammatory T-cell chemokine. Here, we report that levels of CXCL10 change during C. trachomatis infection of cultured cells in a manner dependent on both host and pathogen. Linear modeling of cellular traits associated with CXCL10 levels identified a strong, negative correlation with bacterial burden, suggesting that C. trachomatis actively suppresses CXCL10. We identified the pathogen-encoded factor responsible for this suppression as the chlamydial protease- or proteasome-like activity factor, CPAF. Further, we applied our modeling approach to other host cytokines in response to C. trachomatis and found evidence that RANTES, another T-cell chemoattractant, is actively suppressed by Chlamydia. However, this observed suppression of RANTES is not mediated by CPAF. Overall, our results demonstrate that CPAF suppresses CXCL10 to evade the host cytokine response and that modeling of cellular infection parameters can reveal previously unrecognized facets of host-pathogen interactions.
传染病的易感性是由宿主和病原体之间的复杂相互作用决定的。对于专性细胞内细菌沙眼衣原体引起的感染，免疫激活和疾病表现的变化受宿主遗传多样性和病原体免疫逃避的调节。以前，我们发现了一个与 CXCL10 绝对丰度相关的单核苷酸多态性（rs2869462），CXCL10 是一种促炎 T 细胞趋化因子。在这里，我们报告说，CXCL10 的水平在培养细胞中沙眼衣原体感染期间发生变化，这种变化取决于宿主和病原体。与 CXCL10 水平相关的细胞特征的线性建模确定了与细菌负荷的强烈负相关，表明沙眼衣原体积极抑制 CXCL10。我们确定了导致这种抑制的病原体编码因子是衣原体蛋白酶或蛋白酶体样活性因子，CPA。此外，我们将我们的建模方法应用于其他宿主细胞因子对沙眼衣原体的反应，发现另一种 T 细胞趋化因子 RANTES 也被衣原体积极抑制的证据。然而，这种观察到的 RANTES 抑制不是由 CPA 介导的。总的来说，我们的结果表明，CPA 抑制 CXCL10 以逃避宿主细胞因子反应，并且细胞感染参数的建模可以揭示以前未被认识到的宿主-病原体相互作用方面。
