Kondo Yuka, Suzuki Masahiro, Sato Shingo, Maruyama Soichi, Sei Akiko, Ma Xingyan, Nakano Kota, Doi Yohei, Tsukamoto Kentaro
Laboratory of Bacterial Zoonoses, International Research Center for Infectious Diseases, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
Department of Microbiology, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.
Microbiol Spectr. 2025 Jan 7;13(1):e0192524. doi: 10.1128/spectrum.01925-24. Epub 2024 Nov 29.
a Gram-negative facultative intracellular bacterium, is the etiological agent of cat-scratch disease and also causes bacillary angiomatosis in immunocompromised individuals. Although the ability to promote vascular endothelial cell proliferation differs among species, variations among strains within remain unclear. angiogenic factor A (BafA) and adhesin A (BadA) have been identified as autotransporters of that are involved in endothelial cell proliferation. Although strain-specific differences in the expression of BadA and the VirB/D4 type IV secretion system have been reported, BafA expression among strains has yet to be examined. Therefore, the present study investigated the proliferation-promoting ability of 13 strains from several sources in human umbilical vein endothelial cells (HUVECs). We identified BafA variants 1 and 2 based on the deduced amino acid sequences of its passenger domain. The recombinant proteins of both variants exhibited similar proliferation activity against HUVECs. However, BafA variant 2 strains showed cytotoxicity at a high bacterial inoculum in a direct coculture with HUVECs, which was attenuated in an indirect coculture. These strains, in contrast to BafA variant 1 strains, highly expressed BadA and exhibited bacterial aggregation. Based on a core genome SNP analysis of 50 strains, the BafA variant types corresponded to clades 1-4. These results indicate that vasoproliferative traits differ among clades based on the variant types. Therefore, this study provides a new conceptual framework in which the clades of may predict their pathogenicity in humans.IMPORTANCE species including , , and cause vasoproliferative lesions. Their proliferation-promoting ability in vascular endothelial cells differs among species; however, it is unclear whether these differences exist among strains. We herein showed that strains exhibited variable proliferation-promoting ability and cytotoxicity in vascular endothelial cells, which corresponded to the gene variants possessed by the strains. The expression levels of angiogenic factor A (BafA) and adhesin A, as well as the degree of proliferation-promoting ability and cytotoxicity in endothelial cells, varied among the strains. A core genome SNP analysis of strains using whole genome sequencing data divided strains into four clades, with each clade corresponding to BafA variants 1-4. These results suggest the differential vasoproliferative potency of , with potential implications in clinical management, including risk stratification and predictions of the clinical course.
一种革兰氏阴性兼性胞内细菌，是猫抓病的病原体，也可在免疫功能低下的个体中引起杆菌性血管瘤病。尽管不同种促进血管内皮细胞增殖的能力有所不同，但同种内菌株间的差异仍不清楚。血管生成因子A（BafA）和粘附素A（BadA）已被确定为该菌的自转运蛋白，它们参与内皮细胞增殖。尽管已报道BadA和VirB/D4型IV分泌系统的表达存在菌株特异性差异，但尚未对该菌不同菌株间BafA的表达进行研究。因此，本研究调查了来自多个来源的13株该菌在人脐静脉内皮细胞（HUVECs）中的促增殖能力。我们根据其乘客结构域的推导氨基酸序列鉴定出BafA变体1和2。两种变体的重组蛋白对HUVECs表现出相似的增殖活性。然而，BafA变体2菌株在与HUVECs直接共培养时，在高细菌接种量下表现出细胞毒性，而在间接共培养中这种毒性减弱。与BafA变体1菌株相比，这些菌株高表达BadA并表现出细菌聚集。基于对50株该菌的核心基因组单核苷酸多态性分析，BafA变体类型对应于进化枝1 - 4。这些结果表明，基于变体类型，该菌不同进化枝的血管增殖特性存在差异。因此，本研究提供了一个新的概念框架，其中该菌的进化枝可能预测其对人类的致病性。重要性包括该菌在内的一些菌种会引起血管增殖性病变。它们在血管内皮细胞中的促增殖能力在不同种之间有所不同；然而，这些差异在同种菌株之间是否存在尚不清楚。我们在此表明，该菌菌株在血管内皮细胞中表现出可变的促增殖能力和细胞毒性，这与菌株所拥有的该菌基因变体相对应。血管生成因子A（BafA）和粘附素A的表达水平，以及在内皮细胞中的促增殖能力和细胞毒性程度，在不同菌株间有所不同。使用全基因组测序数据对该菌菌株进行的核心基因组单核苷酸多态性分析将菌株分为四个进化枝，每个进化枝对应BafA变体1 - 4。这些结果提示了该菌不同的血管增殖潜能，对临床管理具有潜在影响，包括风险分层和临床病程预测。
