Cell Biology and Toxicology ( IF 5.3 ) Pub Date : 2021-03-02 , DOI: 10.1007/s10565-021-09587-z Prajita Paul 1 , Paritosh Patel 1 , Suresh K Verma 1 , Pragyan Mishra 1 , Bikash R Sahu 1 , Pritam Kumar Panda 1 , Gajraj Singh Kushwaha 2 , Shantibhusan Senapati 3 , Namrata Misra 1, 2 , Mrutyunjay Suar 1
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The key to bacterial virulence relies on an exquisite balance of signals between microbe and hosts. Bacterial toxin–antitoxin (TA) system is known to play a vital role in response to stress adaptation, drug resistance, biofilm formation, intracellular survival, persistence as well as pathogenesis. In the present study, we investigated the role of Hha-TomB TA system in regulating virulence of Salmonella enterica serovar Typhimurium (S. Typhimurium) in a host model system, where we showed that deletion of hha and tomB genes displayed impaired cell adhesion, invasion, and uptake. The isogenic hha and tomB mutant strain was also found to be deficient in intracellular replication in vitro, with a highly repressed Salmonella Pathogenicity Island-2 (SPI-2) genes and downregulation of Salmonella Pathogenicity Island-1 (SPI-1) genes. In addition, the Δhha and ΔtomB did not show acute colitis in C57BL/6 mice and displayed less dissemination to systemic organs followed by their cecal pathology. The TA mutants also showed reduction in serum cytokine and nitric oxide levels both in vitro and in vivo. However, the inflammation phenotype was restored on complementing strain of TA gene to its mutant strain. In silico studies depicted firm interaction of Hha–TomB complex and the regulatory proteins, namely, SsrA, SsrB, PhoP, and PhoQ. Overall, we demonstrate that this study of Hha–TomB TA system is one of the prime regulating networks essential for S. Typhimurium pathogenesis.
Graphical abstract
中文翻译：
鼠伤寒沙门氏菌中的 Hha-TomB 毒素-抗毒素模块限制了其细胞内存活率并调节宿主免疫反应
细菌毒力的关键依赖于微生物和宿主之间信号的精确平衡。已知细菌毒素-抗毒素 (TA) 系统在应对应激适应、耐药性、生物膜形成、细胞内存活、持久性以及发病机制中发挥着至关重要的作用。在本研究中，我们研究了 Hha-TomB TA 系统在宿主模型系统中调节鼠伤寒沙门氏菌 (S. Typhimurium) 毒力的作用，我们发现hha 和 tomB 基因的缺失显示出细胞粘附、侵袭受损, 和吸收。等基因hha和tomB还发现突变菌株在体外细胞内复制存在缺陷，具有高度抑制的沙门氏菌致病岛 2 (SPI-2) 基因和沙门氏菌致病岛 1 (SPI-1) 基因的下调。此外，Δ hha和 Δ tomB在 C57BL/6 小鼠中没有表现出急性结肠炎，并且表现出较少传播到全身器官，随后是盲肠病理学。TA 突变体在体外和体内也显示出血清细胞因子和一氧化氮水平的降低。然而，炎症表型在 TA 基因与其突变株互补株上恢复。计算机研究描述了 Hha-TomB 复合物与调节蛋白（即 SsrA、SsrB、PhoP 和 PhoQ）之间的牢固相互作用。总的来说，我们证明了这项对 Hha-TomB TA 系统的研究是S必不可少的主要调节网络之一。鼠伤寒的发病机制。
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