Porphyromonas gingivalis is an oral pathogen that promotes dysbiosis by quenching the bactericidal activity of the host immune system while maintaining chronic inflammation, leading to periodontitis. This involves the secretion of virulence factors such as P. gingivalis peptidyl arginine deiminase (PPAD), which converts the C-terminal Arg residues of bacterial and host-derived proteins and peptides into citrulline. We have previously shown that PPAD activity and major fimbriae (containing FimA) are necessary for P. gingivalis to activate Toll-like receptor 2 (TLR2). TLR2 is an important component of the innate immune system and plays a predominant role in the recognition of P. gingivalis by host cells. Here, we extend those findings to show that P. gingivalis strains deficient for PPAD and fimbriae induced almost identical transcriptional profiles in infected primary human gingival fibroblasts (PHGFs), but these differed substantially from the transcriptome elicited by the wild-type ATCC 33277 strain. Apparently, PPAD-modified fimbriae trigger the host cell response to P. gingivalis, as confirmed by showing that the proinflammatory host cell response mediated by TLR2 is dependent on PPAD activity and the presence of fimbriae, with type I fimbriae as the most potent TLR2 activators. We also found that PPAD-modified accessory fimbrial subunits (FimC, FimD, and FimE) alone or in combination are TLR2 ligands in a reporter cell line. Although FimA polymerization to form the fimbrial shaft was not required for TLR2 activation, the secretion and proteolytic maturation of FimA were necessary for signaling by accessory Fim proteins. This was supported by showing that the proinflammatory activation of PHGFs is dependent on PPAD and accessory fimbrial subunits. We conclude that accessory fimbrial subunits are modified by PPAD and stimulate the response to P. gingivalis infection in a TLR2-dependent manner.

中文翻译：

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辅助菌毛亚基和 PPAD 对于牙龈卟啉单胞菌激活 TLR2 是必需的

牙龈卟啉单胞菌是一种口腔病原体，它通过抑制宿主免疫系统的杀菌活性来促进生态失调，同时维持慢性炎症，导致牙周炎。这涉及毒力因子的分泌，例如牙龈卟啉单胞菌肽基精氨酸脱亚胺酶（PPAD），它将细菌和宿主衍生的蛋白质和肽的C端精氨酸残基转化为瓜氨酸。我们之前已经证明，PPAD 活性和主要菌毛（包含 FimA）对于牙龈卟啉单胞菌激活 Toll 样受体2 ( TLR2 )是必需的。TLR2是先天免疫系统的重要组成部分，在识别病原体方面发挥着主导作用。由宿主细胞产生的牙龈卟啉单胞菌。在这里，我们扩展了这些发现，表明缺乏 PPAD 和菌毛的牙龈卟啉单胞菌菌株在受感染的原代人牙龈成纤维细胞 (PHGF) 中诱导出几乎相同的转录谱，但这些转录谱与野生型 ATCC 33277 菌株引起的转录组有很大不同。显然，PPAD 修饰的菌毛触发宿主细胞对牙龈卟啉单胞菌的反应，正如通过显示 TLR2 介导的促炎宿主细胞反应依赖于 PPAD 活性和菌毛的存在所证实的，其中 I 型菌毛是最有效的 TLR2 激活剂。我们还发现，PPAD 修饰的辅助菌毛亚基（FimC、FimD 和 FimE）单独或组合是报告细胞系中的 TLR2 配体。虽然 TLR2 激活不需要 FimA 聚合形成菌毛轴，但 FimA 的分泌和蛋白水解成熟对于辅助 Fim 蛋白的信号传导是必需的。PHGF 的促炎激活依赖于 PPAD 和附属菌毛亚基，这一点得到了支持。我们得出结论，辅助菌毛亚基被 PPAD 修饰并刺激对牙龈卟啉单胞菌的反应以 TLR2 依赖性方式进行感染。