Talyansky Yuli, Nielsen Travis B, Yan Jun, Carlino-Macdonald Ulrike, Di Venanzio Gisela, Chakravorty Somnath, Ulhaq Amber, Feldman Mario F, Russo Thomas A, Vinogradov Evgeny, Luna Brian, Wright Meredith S, Adams Mark D, Spellberg Brad
Department of Molecular Microbiology & Immunology, University of Southern California, Los Angeles, California, United States of America.
Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
PLoS Pathog. 2021 Feb 2;17(2):e1009291. doi: 10.1371/journal.ppat.1009291. eCollection 2021 Feb.
Acinetobacter baumannii is a highly antibiotic-resistant bacterial pathogen for which novel therapeutic approaches are needed. Unfortunately, the drivers of virulence in A. baumannii remain uncertain. By comparing genomes among a panel of A. baumannii strains we identified a specific gene variation in the capsule locus that correlated with altered virulence. While less virulent strains possessed the intact gene gtr6, a hypervirulent clinical isolate contained a spontaneous transposon insertion in the same gene, resulting in the loss of a branchpoint in capsular carbohydrate structure. By constructing isogenic gtr6 mutants, we confirmed that gtr6-disrupted strains were protected from phagocytosis in vitro and displayed higher bacterial burden and lethality in vivo. Gtr6+ strains were phagocytized more readily and caused lower bacterial burden and no clinical illness in vivo. We found that the CR3 receptor mediated phagocytosis of gtr6+, but not gtr6-, strains in a complement-dependent manner. Furthermore, hypovirulent gtr6+ strains demonstrated increased virulence in vivo when CR3 function was abrogated. In summary, loss-of-function in a single capsule assembly gene dramatically altered virulence by inhibiting complement deposition and recognition by phagocytes across multiple A. baumannii strains. Thus, capsular structure can determine virulence among A. baumannii strains by altering bacterial interactions with host complement-mediated opsonophagocytosis.
鲍曼不动杆菌是一种具有高度抗生素耐药性的细菌病原体，需要新的治疗方法。不幸的是，鲍曼不动杆菌毒力的驱动因素仍不明确。通过比较一组鲍曼不动杆菌菌株的基因组，我们在荚膜位点发现了一个特定的基因变异，该变异与毒力改变相关。毒力较低的菌株拥有完整的gtr6基因，而一株高毒力临床分离株在同一基因中存在自发转座子插入，导致荚膜碳水化合物结构中的一个分支点缺失。通过构建gtr6基因的同基因突变体，我们证实，gtr6基因缺失的菌株在体外可免受吞噬作用，且在体内表现出更高的细菌载量和致死率。gtr6+菌株更容易被吞噬，在体内导致的细菌载量较低且不会引发临床疾病。我们发现，CR3受体以补体依赖的方式介导gtr6+菌株而非gtr6-菌株的吞噬作用。此外，当CR3功能被消除时，低毒力的gtr6+菌株在体内的毒力会增加。总之，单个荚膜组装基因的功能丧失通过抑制补体沉积以及多个鲍曼不动杆菌菌株的吞噬细胞识别，显著改变了毒力。因此，荚膜结构可通过改变细菌与宿主补体介导的调理吞噬作用之间的相互作用来决定鲍曼不动杆菌菌株的毒力。
