Chlamydia trachomatis Co-opts the FGF2 Signaling Pathway to Enhance Infection

The molecular details of Chlamydia trachomatis binding, entry, and spread are incompletely understood, but heparan sulfate proteoglycans (HSPGs) play a role in the initial binding steps. As cell surface HSPGs facilitate the interactions of many growth factors with their receptors, we investigated the role of HSPG-dependent growth factors in C. trachomatis infection. Here, we report a novel finding that Fibroblast Growth Factor 2 (FGF2) is necessary and sufficient to enhance C. trachomatis binding to host cells in an HSPG-dependent manner. FGF2 binds directly to elementary bodies (EBs) where it may function as a bridging molecule to facilitate interactions of EBs with the FGF receptor (FGFR) on the cell surface. Upon EB binding, FGFR is activated locally and contributes to bacterial uptake into non-phagocytic cells. We further show that C. trachomatis infection stimulates fgf2 transcription and enhances production and release of FGF2 through a pathway that requires bacterial protein synthesis and activation of the Erk1/2 signaling pathway but that is independent of FGFR activation. Intracellular replication of the bacteria results in host proteosome-mediated degradation of the high molecular weight (HMW) isoforms of FGF2 and increased amounts of the low molecular weight (LMW) isoforms, which are released upon host cell death. Finally, we demonstrate the in vivo relevance of these findings by showing that conditioned medium from C. trachomatis infected cells is enriched for LMW FGF2, accounting for its ability to enhance C. trachomatis infectivity in additional rounds of infection. Together, these results demonstrate that C. trachomatis utilizes multiple mechanisms to co-opt the host cell FGF2 pathway to enhance bacterial infection and spread.目前人们对沙眼衣原体（Chlamydia trachomatis）的黏附、入侵及播散的分子机制尚不完全明确，但硫酸乙酰肝素蛋白聚糖（HSPGs）参与了其初始黏附过程。由于细胞表面的HSPGs可介导多种生长因子与其受体的相互作用，我们探究了依赖HSPG的生长因子在沙眼衣原体感染中的作用。本研究首次发现，成纤维细胞生长因子2（FGF2）可通过依赖HSPG的方式，足以且必需地增强沙眼衣原体对宿主细胞的黏附能力。FGF2可直接结合原体（EBs），可能作为桥接分子促进原体与细胞表面的成纤维细胞生长因子受体（FGFR）结合。原体黏附宿主细胞后，FGFR会被局部激活，进而促进细菌被非吞噬细胞摄取。我们进一步证实，沙眼衣原体感染可通过依赖细菌蛋白质合成且激活Erk1/2信号通路，但不依赖FGFR激活的途径，刺激fgf2基因转录并促进FGF2的产生与释放。细菌的胞内复制会导致宿主蛋白酶体降解FGF2的高分子量（HMW）同工型，同时使低分子量（LMW）同工型的含量升高，这类同工型会在宿主细胞死亡后被释放。最后，我们通过实验证明，沙眼衣原体感染的细胞所分泌的条件培养基中富含LMW FGF2，这解释了其可在后续感染循环中增强沙眼衣原体感染能力的机制。综上，本研究结果表明，沙眼衣原体可通过多种机制劫持宿主细胞的FGF2通路，以增强自身的感染与播散能力。