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Stress-induced inactivation of the Staphylococcus aureus purine biosynthesis repressor leads to hypervirulence

Mariya I. Goncheva,Ronald S. Flannagan,Brigid E. Sterling,Holly A. Laakso,N. Friedrich,Julienne C. Kaiser,D. Watson,C. Wilson,J. Sheldon,M. McGavin,P. Kiser,D. Heinrichs

Published 2019 in Nature Communications

ABSTRACT

Staphylococcus aureus is a significant cause of human infection. Here, we demonstrate that mutations in the transcriptional repressor of purine biosynthesis, purR, enhance the pathogenic potential of S. aureus. Indeed, systemic infection with purR mutants causes accelerated mortality in mice, which is due to aberrant up-regulation of fibronectin binding proteins (FnBPs). Remarkably, purR mutations can arise upon exposure of S. aureus to stress, such as an intact immune system. In humans, naturally occurring anti-FnBP antibodies exist that, while not protective against recurrent S. aureus infection, ostensibly protect against hypervirulent S. aureus infections. Vaccination studies support this notion, where anti-Fnb antibodies in mice protect against purR hypervirulence. These findings provide a novel link between purine metabolism and virulence in S. aureus. PurR acts as transcriptional repressor of purine biosynthesis genes in some bacterial species. Here, the authors show that purR mutations can arise in Staphylococcus aureus upon exposure to stress, leading to upregulation of fibronectin-binding proteins and increased virulence.

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