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

Abstract

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) pathway 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, the ⌬ArcA mutant was attenuated but the ⌬ArcB mutant was hyperattenuated, revealing an unexpected tissue-specific role for citrulline metabolism in pathogenesis. When mice defective for the arginine-dependent production of nitric oxide (iNOS ؊/؊ ) were infected with the ⌬ArcA mutant, cutaneous virulence was rescued, demonstrating 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 virulence by which S. pyogenes uses its metabolism to modulate innate immunity through depletion of an essential host nutrient.

Citrulline Protects Streptococcus pyogenes from Acid Stress Using the Arginine Deiminase Pathway and the F1Fo-ATPase

“…Common, noninvasive soft tissue infections include bacterial pharyngitis and impetigo, in addition to the less common but invasive and often life-threatening necrotizing fasciitis and immune-pathological syndromes like rheumatic fever (6). It was recently discovered that mutations that blocked the ability of S. pyogenes to catabolize arginine attenuated virulence in a murine model of soft tissue infection (5). However, mutants that block catabolism of citrulline resulted in hyperattenuation (5), revealing an unexpected tissue-specific and arginine-independent role for citrulline metabolism in pathogenesis.…”

“…In the Gram-positive pathogen Streptococcus pyogenes (group A streptococcus), it has recently been shown that the ADI pathway metabolite citrulline makes an unexpected arginine-independent contribution to both colonization and virulence (5). This human pathogen is responsible for a large number of diseases that range in severity and invasiveness (6).…”

Immunosuppressive Effects of Arginine Deiminase From Streptococcus Pyogenes

“…Экспрессия AД S. pyogenes кодируется опе-роном Arc, который состоит из трех ферментов: ArcA, ArcB, и ArcC, соответствующих АД, орни-тинкарбамоилтрансферазе и карбаматкиназе [19] (рис. 2).…”

“…Карбаматкиназа осуществляет перенос фосфатной группы с карбамоилфосфа-та на ADP, таким образом, синтезируются ATP и NH 3 [18]. В результате из молекулы аргинина образуется одна молекула СО 2 , одна молекула АТФ и две молекулы NH 3 [19]. Предполагаемая роль системы АД состоит в обеспечении бакте-рий ATP, биосинтезе цитрулина или пирими-динов, осуществляемом карбамоилфосфатазой,…”

“…Дополнительным доказа-тельством несостоятельности iNOS при стрепто-кокковой инфекции было недостаточно значимое повышение вирулентности S. pyogenes у iNOS-дефицитных мышей по сравнению с контроль-ными животными. Эти данные говорят в пользу того, что при инфекции, вызванной S. pyogenes дикого типа, способность iNOS генерировать NO подавляется за счет деплеции субстрата для этого фермента [19]. Учитывая описанные выше отли-чия метаболизма аргинина в макрофагах мыши и человека, можно предположить, что послед-ствия дефицита аргинина, вызванные активно-стью АД, при стрептококковой инфекции у чело-века будут отличаться от таковых у мыши.…”