Department of Oral Microbiology and Immunology, School of Dentistry, Seoul National University, Seoul, Korea.
Dental Research Institute, Seoul National University, Seoul, Korea.
Mol Oral Microbiol. 2016 Dec;31(6):457-471. doi: 10.1111/omi.12139. Epub 2015 Nov 13.
In the pathogenesis of periodontitis, Porphyromonas gingivalis plays a role as a keystone pathogen that manipulates host immune responses leading to dysbiotic oral microbial communities. Arg-gingipains (RgpA and RgpB) and Lys-gingipain (Kgp) are responsible for the majority of bacterial proteolytic activity and play essential roles in bacterial virulence. Therefore, gingipains are often considered as therapeutic targets. This study investigated the role of gingipains in the modulation by P. gingivalis of phagocytosis of Tannerella forsythia by macrophages. Phagocytosis of T. forsythia was significantly enhanced by coinfection with P. gingivalis in a multiplicity of infection-dependent and gingipain-dependent manner. Mutation of either Kgp or Rgp in the coinfecting P. gingivalis resulted in attenuated enhancement of T. forsythia phagocytosis. Inhibition of coaggregation between the two bacterial species reduced phagocytosis of T. forsythia in mixed infection, and this coaggregation was dependent on gingipains. Inhibition of gingipain protease activities in coinfecting P. gingivalis abated the coaggregation and the enhancement of T. forsythia phagocytosis. However, the direct effect of protease activities of gingipains on T. forsythia seemed to be minimal. Although most of the phagocytosed T. forsythia were cleared in infected macrophages, more T. forsythia remained in cells coinfected with gingipain-expressing P. gingivalis than in cells coinfected with the gingipain-null mutant or infected only with T. forsythia at 24 and 48 h post-infection. Collectively, these results suggest that P. gingivalis, mainly via its gingipains, alters the clearance of T. forsythia, and provide some insights into the role of P. gingivalis as a keystone pathogen.
在牙周炎的发病机制中，牙龈卟啉单胞菌（Porphyromonas gingivalis）作为一种关键病原体，操纵宿主免疫反应，导致口腔微生物群落失调。Arg-牙龈蛋白酶（RgpA 和 RgpB）和 Lys-牙龈蛋白酶（Kgp）负责大部分细菌蛋白水解活性，并在细菌毒力中发挥重要作用。因此，牙龈蛋白酶常被视为治疗靶点。本研究探讨了牙龈蛋白酶在牙龈卟啉单胞菌调节巨噬细胞吞噬福赛拟杆菌（Tannerella forsythia）中的作用。在感染复数和牙龈蛋白酶依赖性方式下，牙龈卟啉单胞菌与福赛拟杆菌的共感染显著增强了福赛拟杆菌的吞噬作用。在共感染的牙龈卟啉单胞菌中突变 Kgp 或 Rgp 均导致福赛拟杆菌吞噬作用减弱。两种细菌之间的共聚集被抑制，混合感染中福赛拟杆菌的吞噬作用降低，这种共聚集依赖于牙龈蛋白酶。在共感染的牙龈卟啉单胞菌中抑制牙龈蛋白酶的蛋白酶活性减弱了共聚集和福赛拟杆菌的吞噬作用。然而，牙龈蛋白酶的蛋白酶活性对福赛拟杆菌的直接影响似乎很小。虽然大多数被吞噬的福赛拟杆菌在感染的巨噬细胞中被清除，但在共感染表达牙龈蛋白酶的牙龈卟啉单胞菌的细胞中，与共感染牙龈蛋白酶缺失突变体或仅感染福赛拟杆菌的细胞相比，24 和 48 小时后仍有更多的福赛拟杆菌留在细胞中。综上所述，这些结果表明，牙龈卟啉单胞菌主要通过其牙龈蛋白酶改变了福赛拟杆菌的清除率，为牙龈卟啉单胞菌作为关键病原体的作用提供了一些见解。
