Department of Microbiology, New York University Grossman School of Medicine, New York, NY, USA.
Institute for Comparative Genomics, American Museum of Natural History, New York, NY, USA.
Nat Microbiol. 2021 Jun;6(6):731-745. doi: 10.1038/s41564-021-00890-3. Epub 2021 Apr 19.
Staphylococcus aureus has evolved into diverse lineages, known as clonal complexes (CCs), which exhibit differences in the coding sequences of core virulence factors. Whether these alterations affect functionality is poorly understood. Here, we studied the highly polymorphic pore-forming toxin LukAB. We discovered that the LukAB toxin variants produced by S. aureus CC30 and CC45 kill human phagocytes regardless of whether CD11b, the previously established LukAB receptor, is present, and instead target the human hydrogen voltage-gated channel 1 (HVCN1). Biochemical studies identified the domain within human HVCN1 that drives LukAB species specificity, enabling the generation of humanized HVCN1 mice with enhanced susceptibility to CC30 LukAB and to bloodstream infection caused by CC30 S. aureus strains. Together, this work advances our understanding of an important S. aureus toxin and underscores the importance of considering genetic variation in characterizing virulence factors and understanding the tug of war between pathogens and the host.
金黄色葡萄球菌已经进化成不同的谱系，称为克隆复合体（CC），它们在核心毒力因子的编码序列上表现出差异。这些改变是否影响功能尚不清楚。在这里，我们研究了高度多态的孔形成毒素 LukAB。我们发现，由金黄色葡萄球菌 CC30 和 CC45 产生的 LukAB 毒素变体无论是否存在先前确定的 LukAB 受体 CD11b，都能杀死人类吞噬细胞，而是靶向人类氢电压门控通道 1（HVCN1）。生化研究确定了人类 HVCN1 中驱动 LukAB 物种特异性的结构域，从而能够生成对 CC30 LukAB 敏感性增强的人源化 HVCN1 小鼠，并对由 CC30 金黄色葡萄球菌菌株引起的血流感染产生易感性。总的来说，这项工作增进了我们对一种重要的金黄色葡萄球菌毒素的理解，并强调了在描述毒力因子和理解病原体与宿主之间的拉锯战时，考虑遗传变异的重要性。
