Genetic variation in the MacAB-TolC efflux pump influences pathogenesis of invasive Salmonella isolates from Africa.

Jared D Honeycutt,Liliana M Massis,Susan M Brewer,Yan Li,Denise M Monack,Rocío Canals,Nicolas Wenner,Sky W Brubaker,Phoom Chairatana,Jay C D Hinton,Siân V Owen

doi:10.1371/journal.ppat.1008763

Abstract

The various sub-species of Salmonella enterica cause a range of disease in human hosts. The human-adapted Salmonella enterica serovar Typhi enters the gastrointestinal tract and invades systemic sites to cause enteric (typhoid) fever. In contrast, most non-typhoidal serovars of Salmonella are primarily restricted to gut tissues. Across Africa, invasive non-typhoidal Salmonella (iNTS) have emerged with an ability to spread beyond the gastrointestinal tract and cause systemic bloodstream infections with increased morbidity and mortality. To investigate this evolution in pathogenesis, we compared the genomes of African iNTS isolates with other Salmonella enterica serovar Typhimurium and identified several macA and macB gene variants unique to African iNTS. MacAB forms a tripartite efflux pump with TolC and is implicated in Salmonella pathogenesis. We show that macAB transcription is upregulated during macrophage infection and after antimicrobial peptide exposure, with macAB transcription being supported by the PhoP/Q two-component system. Constitutive expression of macAB improves survival of Salmonella in the presence of the antimicrobial peptide C18G. Furthermore, these macAB variants affect replication in macrophages and influence fitness during colonization of the murine gastrointestinal tract. Importantly, the infection outcome resulting from these macAB variants depends upon both the Salmonella Typhimurium genetic background and the host gene Nramp1, an important determinant of innate resistance to intracellular bacterial infection. The variations we have identified in the MacAB-TolC efflux pump in African iNTS may reflect evolution within human host populations that are compromised in their ability to clear intracellular Salmonella infections.

Highlights

IntroductionWith an estimated 95 million annual cases, non-typhoidal Salmonella (NTS) infection is typically characterized by severe but self-resolving gastroenteritis in otherwise healthy people [1,2,3]
Salmonella infections continue to be a significant challenge for human health
We show that regulation of macAB transcription depends, in part, on the key Salmonella virulence system PhoP/Q and that expression of MacAB improves Salmonella resistance to an antimicrobial peptide

Summary

Introduction

With an estimated 95 million annual cases, non-typhoidal Salmonella (NTS) infection is typically characterized by severe but self-resolving gastroenteritis in otherwise healthy people [1,2,3]. Typhoid and paratyphoid fever cases number more than 14 million annually and are characterized by invasive, bloodstream infection by Salmonella serovars Typhi and Paratyphi, respectively [4]. Risk for typhoid disease remains high in geographic areas with inadequate sanitation infrastructure as the infectious cycle relies on human-to-human transmission. While some humans can become asymptomatic chronic carriers, untreated typhoid fever is often fatal [3]. The 1% case mortality of typhoid fever is similar to that of gastroenteritis associated with NTS [2,4,5]

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Conclusion