Genetic variation in the MacAB-TolC efflux pump influences pathogenesis of invasive Salmonella isolates from Africa.
ATP-Binding Cassette Transporters
/ genetics
Animals
Bacterial Proteins
/ genetics
Cell Lineage
Colitis
/ chemically induced
DNA Mutational Analysis
Disease Models, Animal
Genetic Variation
Macrophages
/ immunology
Mice
Mice, Inbred C57BL
Salmonella Infections, Animal
/ immunology
Salmonella typhimurium
/ immunology
Virus Replication
Journal
PLoS pathogens
ISSN: 1553-7374
Titre abrégé: PLoS Pathog
Pays: United States
ID NLM: 101238921
Informations de publication
Date de publication:
08 2020
08 2020
Historique:
received:
01
05
2020
accepted:
30
06
2020
entrez:
25
8
2020
pubmed:
25
8
2020
medline:
20
9
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 32834002
doi: 10.1371/journal.ppat.1008763
pii: PPATHOGENS-D-20-00892
pmc: PMC7446830
doi:
Substances chimiques
ATP-Binding Cassette Transporters
0
Bacterial Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1008763Subventions
Organisme : NIAID NIH HHS
ID : R01 AI116059
Pays : United States
Organisme : NIAID NIH HHS
ID : T32 AI007290
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007276
Pays : United States
Organisme : Wellcome Trust
ID : 106914/Z/15/Z
Pays : United Kingdom
Déclaration de conflit d'intérêts
I have read the journal's policy and the authors of this manuscript have the following competing interests: Rocío Canals currently works for GSK Vaccines Institute for Global Health. All other authors have no competing interests.
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