Diversification and Evolution of Vancomycin-Resistant Enterococcus faecium during Intestinal Domination.
Krista A Dubin, Deepti Mathur, Peter T McKenney, Bradford P Taylor, Eric R Littmann, Jonathan U Peled, Marcel R M van den Brink, Ying Taur, Eric G Pamer, Joao B Xavier
Author Information
Krista A Dubin: Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Deepti Mathur: Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Peter T McKenney: Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA. ORCID
Bradford P Taylor: Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Eric R Littmann: Center for Microbes, Inflammation and Cancer, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Jonathan U Peled: Adult Bone Marrow Transplantation Service, Memorial Hospital, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York, USA.
Marcel R M van den Brink: Adult Bone Marrow Transplantation Service, Memorial Hospital, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York, USA.
Ying Taur: Infectious Diseases Service, Memorial Hospital, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Eric G Pamer: Center for Microbes, Inflammation and Cancer, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA pamere@mskcc.org xavierj@mskcc.org.
Joao B Xavier: Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA pamere@mskcc.org xavierj@mskcc.org.
Vancomycin-resistant (VRE) is a leading cause of hospital-acquired infections. This is particularly true in immunocompromised patients, where the damage to the microbiota caused by antibiotics can lead to VRE domination of the intestine, increasing a patient's risk for bloodstream infection. In previous studies we observed that the intestinal domination by VRE of patients hospitalized to receive allogeneic bone marrow transplantation can persist for weeks, but little is known about subspecies diversification and evolution during prolonged domination. Here we combined a longitudinal analysis of patient data and experiments to reveal previously unappreciated subspecies dynamics during VRE domination that appeared to be stable from 16S rRNA microbiota analyses. Whole-genome sequencing of isolates obtained from sequential stool samples provided by VRE-dominated patients revealed an unanticipated level of VRE population complexity that evolved over time. In experiments with ampicillin-treated mice colonized with a single CFU, VRE rapidly diversified and expanded into distinct lineages that competed for dominance. Mathematical modeling shows that evolution follows mostly a parabolic fitness landscape, where each new mutation provides diminishing returns and, in the setting of continuous ampicillin treatment, reveals a fitness advantage for mutations in penicillin-binding protein 5 () that increase resistance to ampicillin. Our results reveal the rapid diversification of host-colonizing VRE populations, with implications for epidemiologic tracking of in-hospital VRE transmission and susceptibility to antibiotic treatment.
