c-di-AMP Is Essential for the Virulence of Enterococcus faecalis .

Publisher: American Society For Microbiology Country of Publication: United States NLM ID: 0246127 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1098-5522 (Electronic) Linking ISSN: 00199567 NLM ISO Abbreviation: Infect Immun Subsets: MEDLINE

Publication: Washington, DC : American Society For Microbiology
Original Publication: [Bethesda, Md.] American Society for Microbiology.

Dinucleoside Phosphates/*physiology ; Enterococcus faecalis/*pathogenicity; Animals ; Biofilms ; Enterococcus faecalis/drug effects ; Enterococcus faecalis/growth & development ; Fimbriae, Bacterial/physiology ; Gene Expression Regulation, Bacterial ; Gram-Positive Bacterial Infections/etiology ; Humans ; Virulence

Second messenger nucleotides are produced by bacteria in response to environmental stimuli and play a major role in the regulation of processes associated with bacterial fitness, including but not limited to osmoregulation, envelope homeostasis, central metabolism, and biofilm formation. In this study, we uncovered the biological significance of c-di-AMP in the opportunistic pathogen Enterococcus faecalis by isolating and characterizing strains lacking genes responsible for c-di-AMP synthesis ( cdaA ) and degradation ( dhhP and gdpP ). Using complementary approaches, we demonstrated that either complete loss of c-di-AMP (Δ cdaA strain) or c-di-AMP accumulation (Δ dhhP , Δ gdpP , and Δ dhhP Δ gdpP strains) drastically impaired general cell fitness and virulence of E. faecalis. In particular, the Δ cdaA strain was highly sensitive to envelope-targeting antibiotics, was unable to multiply and quickly lost viability in human serum or urine ex vivo , and was virtually avirulent in an invertebrate (Galleria mellonella) and in two catheter-associated mouse infection models that recapitulate key aspects of enterococcal infections in humans. In addition to evidence linking these phenotypes to altered activity of metabolite and peptide transporters and inability to maintain osmobalance, we found that the attenuated virulence of the Δ cdaA strain also could be attributed to a defect in Ebp pilus production and activity that severely impaired biofilm formation under both in vitro and in vivo conditions. Collectively, these results demonstrate that c-di-AMP signaling is essential for E. faecalis pathogenesis and a desirable target for drug development.

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R01 DK128805 United States DK NIDDK NIH HHS; R21 AI135158 United States AI NIAID NIH HHS; T90 DE021990 United States DE NIDCR NIH HHS

Keywords: c-di-AMP; enterococcus; osmotic stress; pathogenesis; second messenger nucleotide; stress response; urinary tract infection

0 (Dinucleoside Phosphates)
0 (cyclic diadenosine phosphate)

Date Created: 20210823 Date Completed: 20211122 Latest Revision: 20240704

20240704

PMC8519298

10.1128/IAI.00365-21

34424750