Industrial Systems Biology Lab, Department of Bioinformatics, School of Life Sciences, Bharathidasan University, Tiruchirappalli 620024, Tamil Nadu, India.
Industrial Systems Biology Lab, Department of Bioinformatics, School of Life Sciences, Bharathidasan University, Tiruchirappalli 620024, Tamil Nadu, India.
Gene. 2023 Jun 15;869:147402. doi: 10.1016/j.gene.2023.147402. Epub 2023 Mar 25.
Clostridium botulinum type A is a neurotoxin-producing, spore-forming anaerobic bacterium that causes botulism in humans. The evolutionary genomic context of this organism is not yet known to understand its molecular virulence mechanisms in the human intestinal tract. Hence, this study aimed to investigate the mechanisms underlying virulence and pathogenesis by comparing the genomic contexts across species, serotypes, and subtypes.
A comparative genomic approach was used to analyze evolutionary genomic relationships, intergenomic distances, syntenic blocks, replication origins, and gene abundance with phylogenomic neighbors.
Type A strains have shown genomic proximity to group I strains with distinct accessory genes and vary even within subtypes. Phylogenomic data showed that type C and D strains were distantly related to a group I and group II strains. Synthetic plots indicated that orthologous genes might have evolved from Clostridial ancestry to subtype A3 strains, whereas syntonic out-paralogs might have emerged between subtypes A3 and A1 through α-events. Gene abundance analysis revealed the key roles of genes involved in biofilm formation, cell-cell communication, human diseases, and drug resistance compared to the pathogenic Clostridia. Moreover, we identified 43 unique genes in the type A3 genome, of which 29 were involved in the pathophysiological processes and other genes contributed to amino acid metabolism. The C. botulinum type A3 genome contains 14 new virulence proteins that can provide the ability to confer antibiotic resistance, virulence exertion and adherence to host cells, the host immune system, and mobility of extrachromosomal genetic elements.
The results of our study provide insight into the understanding of new virulence mechanisms to discover new therapeutics for the treatment of human diseases caused by type A3 strains.
A 型肉毒梭菌是一种产神经毒素、形成孢子的厌氧细菌，可导致人类肉毒中毒。目前尚不清楚该生物体的进化基因组背景，以了解其在人类肠道中的分子毒力机制。因此，本研究旨在通过比较种系、血清型和亚型的基因组背景，研究其毒力和发病机制。
采用比较基因组学方法分析进化基因组关系、种间基因距离、共线性块、复制起点和与系统发育邻居的基因丰度。
A 型菌株与 I 组菌株具有密切的基因组关系，具有独特的辅助基因，甚至在亚型内也存在差异。系统发育数据表明，C 型和 D 型菌株与 I 组和 II 组菌株的亲缘关系较远。综合图表明，同源基因可能是从梭状芽胞杆菌祖先进化而来的 A3 型菌株，而 A3 和 A1 亚型之间的同调外假基因可能是通过 α 事件产生的。基因丰度分析表明，与致病性梭状芽胞杆菌相比，参与生物膜形成、细胞间通讯、人类疾病和耐药性的基因发挥着关键作用。此外，我们在 A3 型基因组中发现了 43 个独特的基因，其中 29 个参与了病理生理过程，其他基因则有助于氨基酸代谢。A 型 3 型肉毒梭菌基因组包含 14 种新的毒力蛋白，可提供赋予抗生素耐药性、毒力发挥和对宿主细胞、宿主免疫系统以及染色体外遗传元件的运动能力的能力。
本研究结果为理解新的毒力机制提供了深入了解，为治疗 A3 型菌株引起的人类疾病发现新的治疗方法提供了依据。
