Group A Streptococcus host–pathogen dual crosstalk

Abstract The unfolded protein response (UPR) is a central cellular stress pathway increasingly recognized as a target of microbial manipulation. While viral engagement of the UPR is well documented, far less is known about how bacterial pathogens, particularly extracellular ones, exploit this host stress machinery. Group A Streptococcus (GAS) is an exquisitely human-adapted pathogen capable of causing asymptomatic colonization as well as severe invasive diseases and provides a compelling example. GAS selectively activates the PKR-like endoplasmic reticulum kinase (PERK)–eukaryotic initiation factor 2 (eIF2α)–activating transcription factor 4 (ATF4) arm of the UPR, driving host asparagine (Asn) biosynthesis. The bacterium then imports this Asn to boost its metabolic activity, growth, and virulence, establishing a direct metabolic link between host ER stress and GAS pathogenicity. This Asn-driven regulatory circuit parallels the ATF4–Asn axis in cancer biology, where stress-induced Asn production supports metabolic adaptation, proliferation, and resistance to therapy. Together, these insights position Asn as a central metabolic signal at the intersection of host stress responses and GAS virulence.