September 22, 2019  |  

Genome plasticity of agr-defective Staphylococcus aureus during clinical infection.

Authors: Altman, Deena R and Sullivan, Mitchell J and Chacko, Kieran I and Balasubramanian, Divya and Pak, Theodore R and Sause, William E and Kumar, Krishan and Sebra, Robert and Deikus, Gintaras and Attie, Oliver and Rose, Hannah and Lewis, Martha and Fulmer, Yi and Bashir, Ali and Kasarskis, Andrew and Schadt, Eric E and Richardson, Anthony R and Torres, Victor J and Shopsin, Bo and van Bakel, Harm

Therapy for bacteremia caused by Staphylococcus aureus is often ineffective, even when treatment conditions are optimal according to experimental protocols. Adapted subclones, such as those bearing mutations that attenuate agr-mediated virulence activation, are associated with persistent infection and patient mortality. To identify additional alterations in agr-defective mutants, we sequenced and assembled the complete genomes of clone pairs from colonizing and infected sites of several patients in whom S. aureus demonstrated a within-host loss of agr function. We report that events associated with agr inactivation result in agr-defective blood and nares strain pairs that are enriched in mutations compared to pairs from wild-type controls. The random distribution of mutations between colonizing and infecting strains from the same patient, and between strains from different patients, suggests that much of the genetic complexity of agr-defective strains results from prolonged infection or therapy-induced stress. However, in one of the agr-defective infecting strains, multiple genetic changes resulted in increased virulence in a murine model of bloodstream infection, bypassing the mutation of agr and raising the possibility that some changes were selected. Expression profiling correlated the elevated virulence of this agr-defective mutant to restored expression of the agr-regulated ESAT6-like type VII secretion system, a known virulence factor. Thus, additional mutations outside the agr locus can contribute to diversification and adaptation during infection by S. aureus agr mutants associated with poor patient outcomes. Copyright © 2018 Altman et al.

Journal: Infection and immunity
DOI: 10.1128/IAI.00331-18
Year: 2018

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