Microdiversity of Enterococcus faecalis isolates in cases of infective endocarditis: selection of non-synonymous mutations and large deletions is associated with phenotypic modifications

Abstract

Context : Today, infective endocarditis (IE) caused by Enterococcus faecalis represents 10% of all IE and is marked by its difficult management and the frequency of relapses. Although the precise reasons for that remain to be elucidated, the evolution of the culprit strain under selective pressure through microdiversification could be, at least in part, involved. Material and methods : To further study the in situ genetic microdiversity and its possible phenotypic manifestations in E. faecalis IE, we sequenced and compared multiple isolates from the valves, blood culture and joint fluid of five patients who underwent valvular surgery. Growth rate and early biofilm production of selected isolates were also compared. Results : By sequencing a total of 58 E. faecalis genomes, we detected a considerable genomic microdiversity, not only among strains from different anatomical origins, but also between isolates from the same studied cardiac valves. Interestingly, deletions of thousands of bases including the well-known virulence factors ebpA/B/C , and srtC , as well as other large prophage sequences containing genes coding for proteins implicated in platelet binding (PlbA and PlbB) were evidenced. The study of mutations helped unveil common patterns in genes related to the cell cycle as well as central metabolism, suggesting an evolutionary convergence in these isolates. As expected, such modifications were associated with a significant impact on the in-vitro phenotypic heterogeneity, growth, and early biofilm production. Conclusion : Genome modifications associated with phenotypic variations may allow bacterial adaptation to both antibiotic and immune selective pressures, and thus promote relapses.

The population-level impact of Enterococcus faecalis genetics on intestinal colonisation and extraintestinal infection

“…We speculate that the observed strong, but non-statistically significant signals in a single prophage, integrated at chromosome coordinate 1,398,051 to 1,446,151bp in the V583 E. faecalis genome [34], could exemplify a potential locus with small population-wide effects on virulence. Indeed, prophages play a critical role in the pathogenicity of E. faecalis [67][68][69][70] and other bacterial pathogens, such as Staphylococcus aureus [37,71]. Therefore, further studies using even larger genomic datasets than in the present study and adjusting for other important covariates, such as prior antibiotic usage and immune status, are required to fully investigate the impact of the identified E. faecalis prophage in modulating extraintestinal infection.…”

“…We speculate that the observed strong, but non-statistically significant signals in a single prophage, integrated at chromosome coordinate 1,398,051 to 1,446,151bp in the V583 E. faecalis genome [34], could exemplify a potential locus with small population-wide effects on virulence. Indeed, prophages play a critical role in the pathogenicity of E. faecalis [67–70] and other bacterial pathogens, such as Staphylococcus aureus [37,71].…”

Native and Prosthetic Simultaneously Double Valve Infective Endocarditis with Enterococcus faecalis—Case-Based Review

“…When compared to excised valvular specimens by sequencing methods, E. faecalis demonstrated different strains with a high diversity of virulence genes including deletions of ebpA, ebpB, ebpC, and srtC. This could explain the higher duration of infection and replacement rates or the ability to escape the host immune response [ 29 ].…”

Impact of Enterococcus faecalis Endocarditis Treatment on Risk of Relapse

“…This is supported by cases of positive valve culture regardless of the duration of antibiotics administered before surgery, as previously described [ 35–37 ]. This is probably favored by the known natural tolerance to penicillin or phenotypic and genetic changes in enterococci that may confer a selective advantage [ 38 , 39 ].…”