An Extracellular Bacterial Pathogen Modulates Host Metabolism to Regulate Its Own Sensing and Proliferation

Successful infection depends on the ability of the pathogen to gain nutrients from the host. The extracellular pathogenic bacterium group A Streptococcus (GAS) causes a vast array of human diseases. By using the quorum-sensing sil system as a reporter, we found that, during adherence to host cells, GAS delivers streptolysin toxins, creating endoplasmic reticulum stress. This, in turn, increases asparagine (ASN) synthetase expression and the production of ASN. The released ASN is sensed by the bacteria, altering the expression of ∼17% of GAS genes of which about one-third are dependent on the two-component system TrxSR. The expression of the streptolysin toxins is strongly upregulated, whereas genes linked to proliferation are downregulated in ASN absence. Asparaginase, a widely used chemotherapeutic agent, arrests GAS growth in human blood and blocks GAS proliferation in a mouse model of human bacteremia. These results delineate a pathogenic pathway and propose a therapeutic strategy against GAS infections. [Display omitted] •Group A streptococcus (GAS) induces ER stress and asparagine production•Asparagine alters GAS gene expression and increases bacterial multiplication•Expression of streptolysins causing ER stress is augmented in asparagine absence•Asparaginase inhibits GAS bacteremia The human pathogen group A streptococcus delivers streptolysin toxins into host cells, triggering endoplasmic reticulum stress and production of asparagine. Asparagine is utilized by GAS to alter its own gene expression program and enhance proliferation, demonstrating how an extracellular pathogen manipulates host metabolism for its own benefit.