Abstract
Many plasmids encode antibiotic resistance genes. Through conjugation, plasmids can be rapidly disseminated. Previous work identified gut luminal donor/recipient blooms and tissue-lodged plasmid-bearing persister cells of the enteric pathogen Salmonella enterica serovar Typhimurium (S.Tm) that survive antibiotic therapy in host tissues, as factors promoting plasmid dissemination among Enterobacteriaceae. However, the buildup of tissue reservoirs and their contribution to plasmid spread await experimental demonstration. Here, we asked if re-seeding-plasmid acquisition-invasion cycles by S.Tm could serve to diversify tissue-lodged plasmid reservoirs, and thereby promote plasmid spread. Starting with intraperitoneal mouse infections, we demonstrate that S.Tm cells re-seeding the gut lumen initiate clonal expansion. Extended spectrum beta-lactamase (ESBL) plasmid-encoded gut luminal antibiotic degradation by donors can foster recipient survival under beta-lactam antibiotic treatment, enhancing transconjugant formation upon re-seeding. S.Tm transconjugants can subsequently re-enter host tissues introducing the new plasmid into the tissue-lodged reservoir. Population dynamics analyses pinpoint recipient migration into the gut lumen as rate-limiting for plasmid transfer dynamics in our model. Priority effects may be a limiting factor for reservoir formation in host tissues. Overall, our proof-of-principle data indicates that luminal antibiotic degradation and shuttling between the gut lumen and tissue-resident reservoirs can promote the accumulation and spread of plasmids within a host over time.
Highlights
The accumulation of antibiotic resistance genes in pathogenic bacterial strains is an important cause of antibiotic treatment failure
The i.p. infection model mimics tissue reservoirs that are established after systemic spread following gut colonization (Bakkeren et al, 2019; Lam and Monack, 2014; Monack et al, 2004; Stecher et al, 2006)
As natural infections would occur via the oral colonization route, sites that are normally occupied by invading S.Tm cells are less colonized after an i.p. infection compared to an oral infection
Summary
The accumulation of antibiotic resistance genes in pathogenic bacterial strains is an important cause of antibiotic treatment failure. In this work, when we refer to ‘host’, we consistently refer to the mammalian host harbouring enteric bacteria Plasmid spread within such hosts can be aided by tissue-lodged reservoirs of bacterial cells phenotypically recalcitrant to antibiotic therapy (Bakkeren et al, 2019). Persisters can lead to antibiotic treatment failure, but they have important implications for the evolution of antibiotic resistance (Levin-R eisman et al, 2017; Liu et al, 2020; Windels et al, 2019) or virulence (Bakkeren et al, 2020; Diard et al, 2014), and serve as long-term reservoirs promoting the spread of resistance plasmids. The role of this second, non-p ersister, tissue-lodged pathogen population in plasmid dissemination remained to be formally established
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