A Highly Active and Negatively Charged Streptococcus pyogenes Lysin with a Rare d-Alanyl-l-Alanine Endopeptidase Activity Protects Mice against Streptococcal Bacteremia

ABSTRACTBacteriophage endolysins have shown great efficacy in killing Gram-positive bacteria. PlyC, a group C streptococcal phage lysin, represents the most efficient lysin characterized to date, with a remarkably high specificity against different streptococcal species, including the important pathogenStreptococcus pyogenes. However, PlyC is a unique lysin, in terms of both its high activity and structure (two distinct subunits). We sought to discover and characterize a phage lysin active againstS. pyogeneswith an endolysin architecture distinct from that of PlyC to determine if it relies on the same mechanism of action as PlyC. In this study, we identified and characterized an endolysin, termed PlyPy (phagelysin fromS.pyogenes), from a prophage infectingS. pyogenes. Byin silicoanalysis, PlyPy was found to have a molecular mass of 27.8 kDa and a pI of 4.16. It was active against a majority of group A streptococci and displayed high levels of activity as well as binding specificity against group B and C streptococci, while it was less efficient against other streptococcal species. PlyPy showed the highest activity at neutral pH in the presence of calcium and NaCl. Surprisingly, its activity was not affected by the presence of the group A-specific carbohydrate, while the activity of PlyC was partly inhibited. Additionally, PlyPy was activein vivoand could rescue mice from systemic bacteremia. Finally, we developed a novel method to determine the peptidoglycan bond cleaved by lysins and concluded that PlyPy exhibits a rared-alanyl-l-alanine endopeptidase activity. PlyPy thus represents the first lysin characterized fromStreptococcus pyogenesand has a mechanism of action distinct from that of PlyC.

Download Full-text

The Transcriptional Regulator CpsY Is Important for Innate Immune Evasion in Streptococcus pyogenes

Infection and Immunity ◽

10.1128/iai.00925-16 ◽

2016 ◽

Vol 85 (3) ◽

Cited By ~ 2

Author(s):

Luis A. Vega ◽

Kayla M. Valdes ◽

Ganesh S. Sundar ◽

Ashton T. Belew ◽

Emrul Islam ◽

...

Keyword(s):

Streptococcus Pyogenes ◽

Immune Evasion ◽

Immune Cell ◽

Group A Streptococcus ◽

Transcriptional Regulator ◽

Innate Immune ◽

Content Type ◽

Human Host

ABSTRACTAs an exclusively human pathogen,Streptococcus pyogenes(the group A streptococcus [GAS]) has specifically adapted to evade host innate immunity and survive in multiple tissue niches, including blood. GAS can overcome the metabolic constraints of the blood environment and expresses various immunomodulatory factors necessary for survival and immune cell resistance. Here we present our investigation of one such factor, the predicted LysR family transcriptional regulator CpsY. The encoding gene,cpsY, was initially identified as being required for GAS survival in a transposon-site hybridization (TraSH) screen in whole human blood. CpsY is homologous with transcriptional regulators ofStreptococcus mutans(MetR),Streptococcus iniae(CpsY), andStreptococcus agalactiae(MtaR) that regulate methionine transport, amino acid metabolism, resistance to neutrophil-mediated killing, and survivalin vivo. Our investigation indicated that CpsY is involved in GAS resistance to innate immune cells of its human host. However, GAS CpsY does not manifest thein vitrophenotypes of its homologs in other streptococcal species. GAS CpsY appears to regulate a small set of genes that is markedly different from the regulons of its homologs. The differential expression of these genes depends on the growth medium, and CpsY modestly influences their expression. The GAS CpsY regulon includes known virulence factors (mntE,speB,spd,nga[spn],prtS[SpyCEP], andsse) and cell surface-associated factors of GAS (emm1,mur1.2,sibA[cdhA], andM5005_Spy0500). Intriguingly, the loss of CpsY in GAS does not result in virulence defects in murine models of infection, suggesting that CpsY function in immune evasion is specific to the human host.

Download Full-text

SpyAD, a Moonlighting Protein of Group A Streptococcus Contributing to Bacterial Division and Host Cell Adhesion

Infection and Immunity ◽

10.1128/iai.00064-14 ◽

2014 ◽

Vol 82 (7) ◽

pp. 2890-2901 ◽

Cited By ~ 11

Author(s):

Marilena Gallotta ◽

Giovanni Gancitano ◽

Giampiero Pietrocola ◽

Marirosa Mora ◽

Alfredo Pezzicoli ◽

...

Keyword(s):

Cell Division ◽

Mammalian Cells ◽

Group A Streptococcus ◽

Host Cells ◽

Knockout Mutant ◽

Content Type ◽

Moonlighting Protein ◽

Group A

ABSTRACTGroup A streptococcus (GAS) is a human pathogen causing a wide repertoire of mild and severe diseases for which no vaccine is yet available. We recently reported the identification of three protein antigens that in combination conferred wide protection against GAS infection in mice. Here we focused our attention on the characterization of one of these three antigens, Spy0269, a highly conserved, surface-exposed, and immunogenic protein of unknown function. Deletion of thespy0269gene in a GAS M1 isolate resulted in very long bacterial chains, which is indicative of an impaired capacity of the knockout mutant to properly divide. Confocal microscopy and immunoprecipitation experiments demonstrated that the protein was mainly localized at the cell septum and could interactin vitrowith the cell division protein FtsZ, leading us to hypothesize that Spy0269 is a member of the GAS divisome machinery. Predicted structural domains and sequence homologies with known streptococcal adhesins suggested that this antigen could also play a role in mediating GAS interaction with host cells. This hypothesis was confirmed by showing that recombinant Spy0269 could bind to mammalian epithelial cellsin vitroand thatLactococcus lactisexpressing Spy0269 on its cell surface could adhere to mammalian cellsin vitroand to mice nasal mucosain vivo. On the basis of these data, we believe that Spy0269 is involved both in bacterial cell division and in adhesion to host cells and we propose to rename this multifunctional moonlighting protein as SpyAD (StreptococcuspyogenesAdhesion andDivision protein).

Download Full-text

CovRS-Regulated Transcriptome Analysis of a Hypervirulent M23 Strain of Group A Streptococcus pyogenes Provides New Insights into Virulence Determinants

Journal of Bacteriology ◽

10.1128/jb.00511-15 ◽

2015 ◽

Vol 197 (19) ◽

pp. 3191-3205 ◽

Cited By ~ 13

Author(s):

Yun-Juan Bao ◽

Zhong Liang ◽

Jeffrey A. Mayfield ◽

Shaun W. Lee ◽

Victoria A. Ploplis ◽

...

Keyword(s):

Streptococcus Pyogenes ◽

Broad Spectrum ◽

Virulence Genes ◽

Expression Profiles ◽

Altered Expression ◽

Content Type ◽

Metabolic Genes ◽

A Genome ◽

Group A ◽

Regulated Gene Expression

ABSTRACTThe two-componentcontrolofvirulence (Cov) regulator (R)-sensor (S) (CovRS) regulates the virulence ofStreptococcus pyogenes(group AStreptococcus[GAS]). Inactivation of CovS during infection switches the pathogenicity of GAS to a more invasive form by regulating transcription of diverse virulence genes via CovR. However, the manner in which CovRS controls virulence through expression of extended gene families has not been fully determined. In the current study, the CovS-regulated gene expression profiles of a hypervirulentemm23GAS strain (M23ND/CovS negative [M23ND/CovS−]) and a noninvasive isogenic strain (M23ND/CovS+), under different growth conditions, were investigated. RNA sequencing identified altered expression of ∼349 genes (18% of the chromosome). The data demonstrated that M23ND/CovS−achieved hypervirulence by allowing enhanced expression of genes responsible for antiphagocytosis (e.g.,hasABC), by abrogating expression of toxin genes (e.g.,speB), and by compromising gene products with dispensable functions (e.g.,sfb1). Among these genes, several (e.g.,parEandparC) were not previously reported to be regulated by CovRS. Furthermore, the study revealed that CovS also modulated the expression of a broad spectrum of metabolic genes that maximized nutrient utilization and energy metabolism during growth and dissemination, where the bacteria encounter large variations in available nutrients, thus restructuring metabolism of GAS for adaption to diverse growth environments. From constructing a genome-scale metabolic model, we identified 16 nonredundant metabolic gene modules that constitute unique nutrient sources. These genes were proposed to be essential for pathogen growth and are likely associated with GAS virulence. The genome-wide prediction of genes associated with virulence identifies new candidate genes that potentially contribute to GAS virulence.IMPORTANCEThe CovRS system modulates transcription of ∼18% of the genes in theStreptococcus pyogenesgenome. Mutations that inactivate CovR or CovS enhance the virulence of this bacterium. We determined complete transcriptomes of a naturally CovS-inactivated invasive deep tissue isolate of anemm23strain ofS. pyogenes(M23ND) and its complemented avirulent variant (CovS+). We identified diverse virulence genes whose altered expression revealed a genetic switching of a nonvirulent form of M23ND to a highly virulent strain. Furthermore, we also systematically uncovered for the first time the comparative levels of expression of a broad spectrum of metabolic genes, which reflected different metabolic needs of the bacterium as it invaded deeper tissue of the human host.

Download Full-text

Interspecies Communication among Commensal and Pathogenic Streptococci

mBio ◽

10.1128/mbio.00382-13 ◽

2013 ◽

Vol 4 (4) ◽

Cited By ~ 36

Author(s):

Laura C. Cook ◽

Breah LaSarre ◽

Michael J. Federle

Keyword(s):

Quorum Sensing ◽

Biofilm Formation ◽

Human Pathogens ◽

Streptococcus Dysgalactiae ◽

Interspecies Communication ◽

Content Type ◽

Streptococcal Species ◽

Group A ◽

Group B ◽

Regulated Gene Expression

ABSTRACTQuorum sensing (QS) regulates diverse and coordinated behaviors in bacteria, including the production of virulence factors, biofilm formation, sporulation, and competence development. It is now established that some streptococci utilize Rgg-type proteins in concert with short hydrophobic peptides (SHPs) to mediate QS, and sequence analysis reveals that several streptococcal species contain highly homologous Rgg/SHP pairs. In group A streptococcus (GAS), two SHPs (SHP2 and SHP3 [SHP2/3]) were previously identified to be important in GAS biofilm formation. SHP2/3 are detected by two antagonistic regulators, Rgg2 and Rgg3, which control expression of theshpgenes. In group B streptococcus (GBS), RovS is a known virulence gene regulator and ortholog of Rgg2, whereas no apparent Rgg3 homolog exists. Adjacent torovSis a gene (shp1520) encoding a peptide nearly identical to SHP2. Using isogenic mutant strains and transcriptional reporters, we confirmed that RovS/SHP1520 comprise a QS circuit in GBS. More important, we performed experiments demonstrating that production and secretion of SHP1520 by GBS can modulate Rgg2/3-regulated gene expression in GAS intrans; likewise, SHP2/3 production by GAS can stimulate RovS-mediated gene regulation in GBS. An isolate ofStreptococcus dysgalactiaesubsp.equisimilisalso produced a secreted factor capable of simulating the QS circuits of both GAS and GBS, and sequencing confirms the presence of an orthologous Rgg2/SHP2 pair in this species as well. To our knowledge, this is the first documented case of bidirectional signaling between streptococcal species in coculture and suggests a role for orthologous Rgg/SHP systems in interspecies communication between important human pathogens.IMPORTANCEPathogenic streptococci, such as group A (GAS) and group B (GBS) streptococcus, are able to persist in the human body without causing disease but become pathogenic under certain conditions that are not fully characterized. Environmental cues and interspecies signaling between members of the human flora likely play an important role in the transition to a disease state. Since quorum-sensing (QS) peptides have been consistently shown to regulate virulence factor production in pathogenic species, the ability of bacteria to signal via these peptides may prove to be an important link between the carrier and pathogenic states. Here we provide evidence of a bidirectional QS system between GAS, GBS, andStreptococcus dysgalactiaesubsp.equisimilis, demonstrating the possibility of evolved communication systems between human pathogens.

Download Full-text

The Streptococcal Protease SpeB Antagonizes the Biofilms of the Human Pathogen Staphylococcus aureus USA300 through Cleavage of the Staphylococcal SdrC Protein

Journal of Bacteriology ◽

10.1128/jb.00008-20 ◽

2020 ◽

Vol 202 (11) ◽

Author(s):

Katelyn E. Carothers ◽

Zhong Liang ◽

Jeffrey Mayfield ◽

Deborah L. Donahue ◽

Mijoon Lee ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Proteolytic Activity ◽

Streptococcus Pyogenes ◽

Human Pathogen ◽

Content Type ◽

Functional Studies ◽

Human Proteins ◽

Group A ◽

Biofilm Disruption

ABSTRACT Streptococcus pyogenes, or group A Streptococcus (GAS), is both a pathogen and an asymptomatic colonizer of human hosts and produces a large number of surface-expressed and secreted factors that contribute to a variety of infection outcomes. The GAS-secreted cysteine protease SpeB has been well studied for its effects on the human host; however, despite its broad proteolytic activity, studies on how this factor is utilized in polymicrobial environments are lacking. Here, we utilized various forms of SpeB protease to evaluate its antimicrobial and antibiofilm properties against the clinically important human colonizer Staphylococcus aureus, which occupies niches similar to those of GAS. For our investigation, we used a skin-tropic GAS strain, AP53CovS+, and its isogenic ΔspeB mutant to compare the production and activity of native SpeB protease. We also generated active and inactive forms of recombinant purified SpeB for functional studies. We demonstrate that SpeB exhibits potent biofilm disruption activity at multiple stages of S. aureus biofilm formation. We hypothesized that the surface-expressed adhesin SdrC in S. aureus was cleaved by SpeB, which contributed to the observed biofilm disruption. Indeed, we found that SpeB cleaved recombinant SdrC in vitro and in the context of the full S. aureus biofilm. Our results suggest an understudied role for the broadly proteolytic SpeB as an important factor for GAS colonization and competition with other microorganisms in its niche. IMPORTANCE Streptococcus pyogenes (GAS) causes a range of diseases in humans, ranging from mild to severe, and produces many virulence factors in order to be a successful pathogen. One factor produced by many GAS strains is the protease SpeB, which has been studied for its ability to cleave and degrade human proteins, an important factor in GAS pathogenesis. An understudied aspect of SpeB is the manner in which its broad proteolytic activity affects other microorganisms that co-occupy niches similar to that of GAS. The significance of the research reported herein is the demonstration that SpeB can degrade the biofilms of the human pathogen Staphylococcus aureus, which has important implications for how SpeB may be utilized by GAS to successfully compete in a polymicrobial environment.

Download Full-text

Streptococcus pyogenes evades adaptive immunity through specific IgG glycan hydrolysis

Journal of Experimental Medicine ◽

10.1084/jem.20190293 ◽

2019 ◽

Vol 216 (7) ◽

pp. 1615-1629 ◽

Cited By ~ 2

Author(s):

Andreas Naegeli ◽

Eleni Bratanis ◽

Christofer Karlsson ◽

Oonagh Shannon ◽

Raja Kalluru ◽

...

Keyword(s):

Streptococcus Pyogenes ◽

Vaccine Development ◽

Group A Streptococcus ◽

Invasive Infection ◽

Invasive Infections ◽

Life Threatening ◽

Group A ◽

Specific Igg

Streptococcus pyogenes (Group A streptococcus; GAS) is a human pathogen causing diseases from uncomplicated tonsillitis to life-threatening invasive infections. GAS secretes EndoS, an endoglycosidase that specifically cleaves the conserved N-glycan on IgG antibodies. In vitro, removal of this glycan impairs IgG effector functions, but its relevance to GAS infection in vivo is unclear. Using targeted mass spectrometry, we characterized the effects of EndoS on host IgG glycosylation during the course of infections in humans. Substantial IgG glycan hydrolysis occurred at the site of infection and systemically in the severe cases. We demonstrated decreased resistance to phagocytic killing of GAS lacking EndoS in vitro and decreased virulence in a mouse model of invasive infection. This is the first described example of specific bacterial IgG glycan hydrolysis during infection and thereby verifies the hypothesis that EndoS modifies antibodies in vivo. This mechanisms of immune evasion could have implications for treatment of severe GAS infections and for future efforts at vaccine development.

Download Full-text

JPC-2997, a New Aminomethylphenol with HighIn VitroandIn VivoAntimalarial Activities against Blood Stages of Plasmodium

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.03762-14 ◽

2014 ◽

Vol 59 (1) ◽

pp. 170-177 ◽

Cited By ~ 10

Author(s):

Geoffrey W. Birrell ◽

Marina Chavchich ◽

Arba L. Ager ◽

Hong-Ming Shieh ◽

Gavin D. Heffernan ◽

...

Keyword(s):

Half Life ◽

Multidrug Resistant ◽

Volume Of Distribution ◽

Parasite Line ◽

Content Type ◽

Elimination Half Life ◽

Highly Active ◽

Elimination Half

ABSTRACT4-(tert-Butyl)-2-((tert-butylamino)methyl)-6-(6-(trifluoromethyl)pyridin-3-yl)-phenol (JPC-2997) is a new aminomethylphenol compound that is highly activein vitroagainst the chloroquine-sensitive D6, the chloroquine-resistant W2, and the multidrug-resistant TM90-C2BPlasmodium falciparumlines, with 50% inhibitory concentrations (IC50s) ranging from 7 nM to 34 nM. JPC-2997 is >2,500 times less cytotoxic (IC50s > 35 μM) to human (HepG2 and HEK293) and rodent (BHK) cell lines than the D6 parasite line. In comparison to the chemically related WR-194,965, a drug that had advanced to clinical studies, JPC-2997 was 2-fold more activein vitroagainstP. falciparumlines and 3-fold less cytotoxic. The compound possesses potentin vivosuppression activity againstPlasmodium berghei, with a 50% effective dose (ED50) of 0.5 mg/kg of body weight/day following oral dosing in the Peters 4-day test. The radical curative dose of JPC-2997 was remarkably low, at a total dose of 24 mg/kg, using the modified Thompson test. JPC-2997 was effective in curing threeAotusmonkeys infected with a chloroquine- and pyrimethamine-resistant strain ofPlasmodium vivaxat a dose of 20 mg/kg daily for 3 days. At the doses administered, JPC-2997 appeared to be well tolerated in mice and monkeys. Preliminary studies of JPC-2997 in mice show linear pharmacokinetics over the range 2.5 to 40 mg/kg, a low clearance of 0.22 liters/h/kg, a volume of distribution of 15.6 liters/kg, and an elimination half-life of 49.8 h. The highin vivopotency data and lengthy elimination half-life of JPC-2997 suggest that it is worthy of further preclinical assessment as a partner drug.

Download Full-text

The Mga Regulon but Not Deoxyribonuclease Sda1 of Invasive M1T1 Group A Streptococcus Contributes toIn VivoSelection of CovRS Mutations and Resistance to Innate Immune Killing Mechanisms

Infection and Immunity ◽

10.1128/iai.00857-15 ◽

2015 ◽

Vol 83 (11) ◽

pp. 4293-4303 ◽

Cited By ~ 9

Author(s):

Guanghui Liu ◽

Wenchao Feng ◽

Dengfeng Li ◽

Mengyao Liu ◽

Daniel C. Nelson ◽

...

Keyword(s):

Group A Streptococcus ◽

Regulatory System ◽

Innate Immune ◽

M Protein ◽

Content Type ◽

Group A ◽

Innate Immune Evasion ◽

Selection Of

ABSTRACTInvasive M1T1 group AStreptococcus(GAS) can have a mutation in the regulatory system CovRS, and this mutation can render strains hypervirulent. Interestingly, via mechanisms that are not well understood, the host innate immune system's neutrophils select spontaneous M1T1 GAS CovRS hypervirulent mutants, thereby enhancing the pathogen's ability to evade immune killing. It has been reported that the DNase Sda1 is critical for the resistance of M1T1 strain 5448 to killing in human blood and provides pressure forin vivoselection of CovRS mutations. We reexamined the role of Sda1 in the selection of CovRS mutations and in GAS innate immune evasion. Deletion ofsda1or all DNase genes in M1T1 strain MGAS2221 did not alter emergence of CovRS mutants during murine infection. Deletion ofsda1in strain 5448 resulted in Δsda1mutants with (5448 Δsda1M+strain) and without (5448 Δsda1M−strain) M protein production. The 5448 Δsda1M+strain accumulated CovRS mutationsin vivoand resisted killing in the bloodstream, whereas the 5448 Δsda1M−strain lostin vivoselection of CovRS mutations and was sensitive to killing. The deletion ofemmand a spontaneous Mga mutation in MGAS2221 reduced and preventedin vivoselection for CovRS mutants, respectively. Thus, in contrast to previous reports, Sda1 is not critical forin vivoselection of invasive M1T1 CovRS mutants and GAS resistance to innate immune killing mechanisms. In contrast, M protein and other Mga-regulated proteins contribute to thein vivoselection of M1T1 GAS CovRS mutants. These findings advance the understanding of the progression of invasive M1T1 GAS infections.

Download Full-text

Differences between Macrolide-Resistant and -Susceptible Streptococcus pyogenes: Importance of Clonal Properties in Addition to Antibiotic Consumption

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01133-12 ◽

2012 ◽

Vol 56 (11) ◽

pp. 5661-5666 ◽

Cited By ~ 21

Author(s):

C. Silva-Costa ◽

A. Friães ◽

M. Ramirez ◽

J. Melo-Cristino ◽

Keyword(s):

Streptococcus Pyogenes ◽

Antibiotic Consumption ◽

Macrolide Resistance ◽

Typing Method ◽

Susceptible Population ◽

Content Type ◽

Resistant Population ◽

Changing Patterns ◽

Group A ◽

Two Populations

ABSTRACTA steady decline in macrolide resistance amongStreptococcus pyogenes(group A streptococci [GAS]) in Portugal was reported during 1999 to 2006. This was accompanied by alterations in the prevalence of macrolide resistance phenotypes and in the clonal composition of the population. In order to test whether changes in the macrolide-resistant population reflected the same changing patterns of the overall population, we characterized both macrolide-susceptible and -resistant GAS associated with a diagnosis of tonsillo-pharyngitis recovered in the period from 2000 to 2005 in Portugal. Pulsed-field gel electrophoresis (PFGE) profiling was the best predictor ofemmtype and the only typing method that could discriminate clones associated with macrolide resistance and susceptibility within eachemmtype. Six PFGE clusters were significantly associated with macrolide susceptibility: T3-emm3-ST406, T4-emm4-ST39, T1-emm1-ST28, T6-emm6-ST382, B3264-emm89-ST101/ST408, and T2-emm2-ST55. Four PFGE clusters were associated with macrolide resistance: T4-emm4-ST39, T28-emm28-ST52, T12-emm22-ST46, and T1-emm1-ST28. We found no evidence for frequent ongoing horizontal transfer of macrolide resistance determinants. The diversity of the macrolide-resistant population was lower than that of susceptible isolates. The differences found between the two populations suggest that the macrolide-resistant population of GAS has its own dynamics, independent of the behavior of the susceptible population.

Download Full-text

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

Infection and Immunity ◽

10.1128/iai.00916-13 ◽

2013 ◽

Vol 82 (1) ◽

pp. 233-242 ◽

Cited By ~ 24

Author(s):

Zachary T. Cusumano ◽

Michael E. Watson ◽

Michael G. Caparon

Keyword(s):

Nitric Oxide ◽

Innate Immunity ◽

Streptococcus Pyogenes ◽

Murine Model ◽

Acid Stress ◽

Arginine Deiminase ◽

Content Type ◽

Cutaneous Tissue

ABSTRACTA bacterium's ability to acquire nutrients from its host during infection is an essential component of pathogenesis. For the Gram-positive pathogenStreptococcus pyogenes, catabolism of the amino acid arginine via the arginine deiminase (ADI) pathway supplements energy production and provides protection against acid stressin vitro. Its expression is enhanced in murine models of infection, suggesting an important rolein 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 (ΔArcA) or citrulline (ΔArcB) were attenuated for carriage in a murine model of asymptomatic mucosal colonization. However, in a murine model of inflammatory infection of cutaneous tissue, the ΔArcA mutant was attenuated but the ΔArcB 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 ΔArcA mutant, cutaneous virulence was rescued, demonstrating that the ability ofS. pyogenesto 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 whichS. pyogenesuses its metabolism to modulate innate immunity through depletion of an essential host nutrient.

Download Full-text