Zhao Mao #,Haobo Zhang #,Wentong Cai,Yan Yang,Xinyang Zhang,Fengwei Jiang,Ganwu Li

Infect Immun.2023 Oct 10:e0003923.doi: 10.1128/iai.00039-23. Online ahead of print.

Abstract

Extraintestinal pathogenic  Escherichia coli  (ExPEC) is responsible for severe bloodstream infections in humans and animals. However, the mechanisms underlying ExPEC's serum resistance remain incompletely understood. Through the transposon-directed insertion-site sequencing approach, our previous study identified  nhaA , the gene encoding a Na⁺/H⁺ antiporter, as a crucial factor for infection  in vivo . In this study, we investigated the role of NhaA in ExPEC virulence utilizing both  in vitro  models and systemic infection models involving avian and mammalian animals. Genetic mutagenesis analysis revealed that  nhaA  deletion resulted in filamentous bacterial morphology and rendered the bacteria more susceptible to sodium dodecyl sulfate, suggesting the role of  nhaA  in maintaining cell envelope integrity. The  nhaA  mutant also displayed heightened sensitivity to complement-mediated killing compared to the wild-type strain, attributed to augmented deposition of complement components (C3b and C9). Remarkably, NhaA played a more crucial role in virulence compared to several well-known factors, including Iss, Prc, NlpI, and OmpA. Our findings revealed that NhaA significantly enhanced virulence across diverse human ExPEC prototype strains within B2 phylogroups, suggesting widespread involvement in virulence. Given its pivotal role, NhaA could serve as a potential drug target for tackling ExPEC infections.

Keywords: ExPEC; NhaA; complement system; envelope integrity; serum resistance; virulence.