2203. Genetic variation and altered virulence associated with loss of agr quorum-sensing functionality in patients with Staphylococcus aureus bacteremia
Session: Poster Abstract Session: Host-Pathogen Interactions
Saturday, October 29, 2016
Room: Poster Hall
Background: Although S. aureus infects only a minority of hosts, it easily transitions to a virulent lifestyle. The genetic events associated with this transition are poorly understood. Inactivating mutations in agr, a quorum-sensing virulence regulator, arise and persist during S. aureus infection and are associated with worse outcomes in bacteremic patients. Here, we comprehensively mapped genetic changes accompanying within-host shifts in agr functionality during infection by sequencing S. aureus clones from blood and nasal sites of single patients.

Methods: Complete genomes were obtained for clones from the nares, blood, and in some cases the presumed infection focus of 10 patients from a previous study. Isolates from all 5 patients in that study with agr-defective bacteremia who did not have agr-defective nares or focus of infection isolates were analyzed. For comparison, we analyzed clones from 5 other subjects with agr-positive bacteremia who were nasally colonized with an agr-positive strain. Naturally occurring agr-defective variants, wild type strains in which the agr locus was knocked out, and agr complemented clones were tested for growth, global gene expression, and virulence.

Results: agr-defective mutant blood isolates from patients with a within-host downshift in agr function had more mutated genes compared to blood isolates from homogenously agr-positive infections. The insertions, point mutations, and rearrangements that accompanied invasive infection were patient specific and had minor effects on virulence in conjunction with agr deficiency. However, in one strain, radical genetic events ameliorated the fitness cost imparted by agr inactivation during growth in vitro. They also restored virulence in an animal model of infection, but not in vitro production of toxic exoproteins.

Conclusion: The events and stresses that promote agr mutation result in genomes enriched in mutations unique to each agr-defective mutant. Random mutation patterns and lack of concordance in strains from different patients suggests the genomic complexity of agr-defective mutants is the result of infection, rather than the cause. Although these mutations may favor clonal expansion of S. aureus within patients, they may also create new treatment targets.

Deena Altman, MD1,2, Mitchell Sullivan, PhD2, Kieran Chacko, BA, BS2, Divya Balasubramanian, PhD3, Theodore Pak, AB2, William Sause, PhD3, Krishan Kumar, PhD3, Robert Sebra, Ph.D.2, Gintaras Deikus, PhD2, Oliver Attie, PhD2, Hannah Rose, BS4, Martha Lewis, BS2, Yi Li, PhD4, Ali Bashir, PhD2, Andrew Kasarskis, PhD2, Eric Schadt, PhD2, Victor Torres, Ph.D.3, Bo Shopsin, MD, PhD4 and Harm Van Bakel, PhD2, (1)Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, (2)Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, (3)Department of Microbiology, New York University School of Medicine, New York, NY, (4)Department of Medicine, Division of Infectious Diseases, NYU School of Medicine, New York, NY

Disclosures:

D. Altman, None

M. Sullivan, None

K. Chacko, None

D. Balasubramanian, None

T. Pak, None

W. Sause, None

K. Kumar, None

R. Sebra, None

G. Deikus, None

O. Attie, None

H. Rose, None

M. Lewis, None

Y. Li, None

A. Bashir, None

A. Kasarskis, None

E. Schadt, None

V. Torres, None

B. Shopsin, None

H. Van Bakel, None

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