B-169. PerR Confers Resistance to Phagocytic Killing and Enhances Pharyngeal Colonization of Group A Streptococcus

I. Gryllos1,2, R. Grifantini3, A. Colaprico3, M. E. Cary4, A. Hakansson1,2, D. W. Carey4, M. Suarez-Chavez4, L. A. Kalish1,2, P. D. Mitchell1, G. L. White4, M. R. Wessels1,2;
1Children's Hosp., Boston, MA, 2Harvard Med. Sch., Boston, MA, 3Novartis Vaccines & Diagnostics, Siena, ITALY, 4Oklahoma Univ. Hlth. Sci. Ctr., Oklahoma City, OK.

The peroxide response regulator PerR controls an important oxidative stress adaptation response of group A Streptococcus (Streptococcus pyogenes or GAS). In this study, we aimed to characterize the PerR regulon of M-type 3 GAS and investigate the specific contribution of PerR-regulated gene expression to GAS virulence during human infection. A perR deletion mutant was derived from wild type GAS strain 003Sm by allelic exchange. Comparison of the mutant transcriptome to that of wild type using GAS genomic microarrays identified 42 PerR-dependent genes. Several of these were not previously recognized as PerR-dependent and included genes with predicted function in oxidative stress responses and sugar utilization and transport. Deletion of perR in strain 003Sm was associated with increased susceptibility to phagocytic killing in human blood and by mouse macrophages in vitro, an effect that was dependent on the phagocyte respiratory burst. In addition, the capacity of an isogenic perR mutant to colonize the pharynx was tested in a baboon model of human pharyngeal colonization during competitive infection with wild type GAS. In those studies, wild type bacteria persisted in the pharynx of five baboons for 28 to 42 days, whereas the perR mutant was cleared in 2 of 5 baboons at 24 h and from 4 of 5 animals by day 14. The results of the present investigation support a key role of PerR in GAS adaptive responses in the host and directly associate PerR-dependent gene expression with GAS phagocytic killing resistance and pharyngeal colonization. The diverse functions of PerR-dependent loci also suggest a previously unrecognized role of PerR in GAS physiology that may contribute to increased bacterial fitness in the host.