Streptococcus pyogenes Arginine and Citrulline Catabolism Promotes Infection and Modulates Innate Immunity

A bacterium’s ability to acquire nutrients from its host during infection is an essential component of pathogenesis. For the Gram-positive pathogen Streptococcus pyogenes, catabolism of the amino acid arginine via the arginine deiminase (ADI) path-way supplements energy production and provides protection against acid stress in vitro. Its expression is enhanced in murine models of infection, suggesting an important role in vivo. To gain insight into the function of the ADI pathway in pathogenesis, the virulence of mutants defective in each of its enzymes was examined. Mutants unable to use arginine (ArcA) or citrulline (ArcB) were attenuated for carriage in a murine model of asymptomatic mucosal colonization. However, in a murine model of inflammatory infection of cutaneous tissue, theArcA mutant was attenuated but theArcB mutant was hyperattenuated, re-vealing an unexpected tissue-specific role for citrulline metabolism in pathogenesis. When mice defective for the arginine-de-pendent production of nitric oxide (iNOS/) were infected with theArcA mutant, cutaneous virulence was rescued, demon-strating that the ability of S. pyogenes to utilize arginine was dispensable in the absence of nitric oxide-mediated innate immunity. This work demonstrates the importance of arginine and citrulline catabolism and suggests a novel mechanism of vir-ulence by which S. pyogenes uses its metabolism to modulate innate immunity through depletion of an essential host nutrient. Nutrient acquisition by a pathogen is necessary for the coloni-zation of a host and represents an important aspect of bacte-rial pathogenesis. Identification of bacterial metabolic pathways utilized during an infection can reveal unique targets for nove