Deciphering the role of outer membrane porins in the pathogenesis of Salmonella enterica serovar Typhimurium

Abstract

Porins are highly conserved barrel-shaped proteins bound to the bacterial outer membrane and involved in the selective transport of charged molecules across the membrane. They consist of parallel and anti-parallel and#946; sheets connected by small extracellular loops. The porins make the outer membrane of the bacteria impermeable to a wide range of toxic molecules such as bile salts, antimicrobial peptides, antibiotics, etc. Salmonella Typhimurium has four major porins to maintain the stability of its outer membrane, namely outer membrane protein A (OmpA), outer membrane protein C (OmpC), outer membrane protein D (OmpD), and outer membrane protein F (OmpF). We found that the wild type Salmonella prefers OmpA over other porins while growing inside the murine macrophages. This observation led us to find out the role of OmpA in Salmonella pathogenesis. We found that deletion of OmpA poses a significant impact on the in vitro and the in vivo life of the pathogen. The bacteria lose the integrity of their outer membrane in the absence of OmpA, which further enhances the porosity of the bacterial outer membrane. The enhanced expression of another larger outer membrane porin OmpF in the absence of OmpA was responsible for the increased permeability of the bacterial outer membrane, making the bacteria susceptible to in vitro and in vivo nitrosative stress. The deletion of OmpA interrupts the vacuolar life of the pathogen as well. The OmpA knockout strain was found unable to maintain the stability of the SCV membrane while growing within the host cells and are gradually released into the cytosol. The cytosolic population of the knockout Salmonella activated the autophagy pathway. We further proved that the extracellular loops of OmpA that connect the and#946; sheets maintain the stability of the SCV membrane by retaining LAMP-1 around the intracellular Salmonella. Our study further revealed that OmpA plays an essential role against the cell wall biosynthesis inhibitors (antibiotics- meropenem and ceftazidime) out of all other porin...