scholarly journals d-Alanylation of Teichoic Acids Promotes Group A Streptococcus Antimicrobial Peptide Resistance, Neutrophil Survival, and Epithelial Cell Invasion

2005 ◽  
Vol 187 (19) ◽  
pp. 6719-6725 ◽  
Author(s):  
Sascha A. Kristian ◽  
Vivekanand Datta ◽  
Christopher Weidenmaier ◽  
Rita Kansal ◽  
Iris Fedtke ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Group A Streptococcus ◽  
Teichoic Acid ◽  
Systemic Infection ◽  
Human Neutrophils ◽  
Invasive Infection ◽  
Bacterial Surface ◽  
Innate Defense ◽  
Group A ◽  
Antimicrobial Peptide Resistance

ABSTRACT Group A streptococcus (GAS) is a leading cause of severe, invasive human infections, including necrotizing fasciitis and toxic shock syndrome. An important element of the mammalian innate defense system against invasive bacterial infections such as GAS is the production of antimicrobial peptides (AMPs) such as cathelicidins. In this study, we identify a specific GAS phenotype that confers resistance to host AMPs. Allelic replacement of the dltA gene encoding d-alanine-d-alanyl carrier protein ligase in an invasive serotype M1 GAS isolate led to loss of teichoic acid d-alanylation and an increase in net negative charge on the bacterial surface. Compared to the wild-type (WT) parent strain, the GAS ΔdltA mutant exhibited increased susceptibility to AMP and lysozyme killing and to acidic pH. While phagocytic uptake of WT and ΔdltA mutants by human neutrophils was equivalent, neutrophil-mediated killing of the ΔdltA strain was greatly accelerated. Furthermore, we observed the ΔdltA mutant to be diminished in its ability to adhere to and invade cultured human pharyngeal epithelial cells, a likely proximal step in the pathogenesis of invasive infection. Thus, teichoic acid d-alanylation may contribute in multiple ways to the propensity of invasive GAS to bypass mucosal defenses and produce systemic infection.

scholarly journals A Novel Heme Transporter from the Energy Coupling Factor Family Is Vital for Group A Streptococcus Colonization and Infections

2020 ◽  
Vol 202 (14) ◽  
Author(s):  
Nilanjana Chatterjee ◽  
Laura C. C. Cook ◽  
Kristin V. Lyles ◽  
Hong Anh T. Nguyen ◽  
Darius J. Devlin ◽  
...  
Keyword(s):  
Inductively Coupled Plasma ◽  
Group A Streptococcus ◽  
Bacterial Colonization ◽  
Critical Role ◽  
Systemic Infection ◽  
Energy Coupling ◽  
Coupling Factor ◽  
Iron Complex ◽  
Invasive Infection ◽  
Group A

ABSTRACT Group A streptococcus (GAS) produces millions of infections worldwide, including mild mucosal infections, postinfection sequelae, and life-threatening invasive diseases. During infection, GAS readily acquires nutritional iron from host heme and hemoproteins. Here, we identified a new heme importer, named SiaFGH, and investigated its role in GAS pathophysiology. The SiaFGH proteins belong to a group of transporters with an unknown ligand from the recently described family of energy coupling factors (ECFs). A siaFGH deletion mutant exhibited high streptonigrin resistance compared to the parental strain, suggesting that iron ions or an iron complex is the likely ligand. Iron uptake and inductively coupled plasma mass spectrometry (ICP-MS) studies showed that the loss of siaFGH did not impact GAS import of ferric or ferrous iron, but the mutant was impaired in using hemoglobin iron for growth. Analysis of cells growing on hemoglobin iron revealed a substantial decrease in the cellular heme content in the mutant compared to the complemented strain. The induction of the siaFGH genes in trans resulted in the induction of heme uptake. The siaFGH mutant exhibited a significant impairment in murine models of mucosal colonization and systemic infection. Together, the data show that SiaFGH is a new type of heme importer that is key for GAS use of host hemoproteins and that this system is imperative for bacterial colonization and invasive infection. IMPORTANCE ECF systems are new transporters that take up various vitamins, cobalt, or nickel with a high affinity. Here, we establish the GAS SiaFGH proteins as a new ECF module that imports heme and demonstrate its importance in virulence. SiaFGH is the first heme ECF system described in bacteria. We identified homologous systems in the genomes of related pathogens from the Firmicutes phylum. Notably, GAS and other pathogens that use a SiaFGH-type importer rely on host hemoproteins for a source of iron during infection. Hence, recognizing the function of this noncanonical ABC transporter in heme acquisition and the critical role that it plays in disease has broad implications.

scholarly journals Streptococcus pyogenes evades adaptive immunity through specific IgG glycan hydrolysis

2019 ◽  
Vol 216 (7) ◽  
pp. 1615-1629 ◽  
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.

scholarly journals A Mobile Genetic Element Promotes the Association Between Serotype M28 Group A Streptococcus Isolates and Cases of Puerperal Sepsis

2019 ◽  
Vol 220 (5) ◽  
pp. 882-891 ◽  
Author(s):  
Ira Jain ◽  
Poulomee Sarkar ◽  
Jessica L Danger ◽  
Josette Medicielo ◽  
Roshika Roshika ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Reproductive Tract ◽  
Mobile Genetic Element ◽  
Group A Streptococcus ◽  
Female Reproductive Tract ◽  
Sequencing Analysis ◽  
Messenger Rnas ◽  
Genetic Element ◽  
Puerperal Sepsis ◽  
Group A

AbstractBackgroundBacterial infections following childbirth—so-called puerperal infections—cause morbidity in 5%–10% of all new mothers. At low frequency, the infection can spread to the blood, resulting in life-threatening sepsis known as puerperal sepsis. Pathogens causing puerperal sepsis include group A Streptococcus (GAS), and epidemiological analyses have identified isolates of a single serotype, M28, as being nonrandomly associated with cases of puerperal sepsis. The genomes of serotype M28 GAS isolates harbor a 36.3-kb mobile genetic element of apparent group B Streptococcus origin, termed region of difference 2 (RD2).MethodsThe phenotypic (determined via tissue culture and a vaginal colonization model) and regulatory (determined via RNA sequencing analysis) contributions of RD2 were assessed by comparing parental, RD2 deletion mutant, and complemented mutant serotype M28 GAS strains.ResultsRD2 affords serotype M28 isolates an enhanced ability to adhere to human vaginal epithelial cells and to colonize the female reproductive tract in a mouse model of infection. In addition, RD2 influences the abundance of messenger RNAs from >100 core chromosomal GAS genes.ConclusionsThe data are consistent with RD2 directly, via encoded virulence factors, and indirectly, via encoded regulatory proteins, modifying the virulence potential of GAS and contributing to the decades-old association of serotype M28 isolates with cases of puerperal sepsis.

Cysteine proteinase SpeB from Streptococcus pyogenes – a potent modifier of immunologically important host and bacterial proteins

2011 ◽  
Vol 392 (12) ◽  
pp. 1077-1088 ◽  
Author(s):  
Daniel C. Nelson ◽  
Julia Garbe ◽  
Mattias Collin
Keyword(s):  
Streptococcus Pyogenes ◽  
Group A Streptococcus ◽  
Wide Spectrum ◽  
Cysteine Proteinase ◽  
Complement Components ◽  
Bacterial Surface ◽  
Bacterial Proteins ◽  
Disease States ◽  
Group A ◽  
Important Host

AbstractGroup A streptococcus (Streptococcus pyogenes) is an exclusively human pathogen that causes a wide spectrum of diseases ranging from pharyngitis, to impetigo, to toxic shock, to necrotizing fasciitis. The diversity of these disease states necessitates thatS. pyogenespossess the ability to modulate both the innate and adaptive immune responses. SpeB, a cysteine proteinase, is the predominant secreted protein fromS. pyogenes. Because of its relatively indiscriminant specificity, this enzyme has been shown to degrade the extracellular matrix, cytokines, chemokines, complement components, immunoglobulins, and serum protease inhibitors, to name but a few of the known substrates. Additionally, SpeB regulates other streptococcal proteins by degrading them or releasing them from the bacterial surface. Despite the wealth of literature on putative SpeB functions, there remains much controversy about this enzyme because many of reported activities would produce contradictory physiological results. Here we review all known host and bacterial protein substrates for SpeB, their cleavage sites, and discuss the role of this enzyme in streptococcal pathogenesis based on the current literature.

scholarly journals Streptococcal sepsis and periorbital cellulitis as a complication of influenza in a 4-year-old girl

2020 ◽  
Vol 16 (3) ◽  
pp. 312-315
Author(s):  
Anna Materny ◽  
◽  
Ernest Kuchar ◽  
Keyword(s):  
Toxic Shock Syndrome ◽  
Influenza A ◽  
Bacterial Infections ◽  
Group A Streptococcus ◽  
Rare Complication ◽  
Fatal Outcome ◽  
Systemic Infection ◽  
Streptococcal Toxic Shock Syndrome ◽  
Toxic Shock ◽  
The Right

Influenza may pave the way for some specific bacterial infections. In this case study we present a rare complication of influenza A infection – periorbital cellulitis followed by streptococcal toxic shock syndrome and scarlet fever. A 4-year-old otherwise healthy girl presented with her mother to a general practitioner with fatigue, irritability and fever not responding to antipyretics. Due to the positive rapid influenza diagnostic test, treatment with oseltamivir was implemented. The Quick Strep Test was negative. During the following days, the patient’s condition worsened, leading to an admission to a paediatric otolaryngology unit. Doctors observed an asymmetrical swelling of the lids with exophthalmos of the right eye, pharyngitis, petechiae in skin folds, a strawberry tongue and skin exfoliation on the lips. The patient was treated with intravenous broadspectrum antibiotics (cefotaxime, vancomycin) and underwent drainage of sinuses, without any significant improvement. On the following day, the girl showed signs of systemic infection, confusion and further swelling of both eyes, and therefore was moved to an intensive care unit. Computed tomography of the head showed signs of periorbital cellulitis with destruction of the surrounding bones. After obtaining a positive blood culture for group A streptococcus, penicillin and clindamycin were immediately administered. The patient’s condition improved within 24 hours. The described case emphasises the importance of yearly influenza vaccination, especially in the groups with risk factors like very young age. Early diagnosis of the streptococcal infection as a complication of influenza and a targeted treatment may prevent the potentially fatal outcome in the form of streptococcal toxic shock syndrome.

scholarly journals AR-12 Has a Bactericidal Activity and a Synergistic Effect with Gentamicin against Group A Streptococcus

2021 ◽  
Vol 22 (21) ◽  
pp. 11617
Author(s):  
Nina Tsao ◽  
Ya-Chu Chang ◽  
Sung-Yuan Hsieh ◽  
Tang-Chi Li ◽  
Ching-Chen Chiu ◽  
...  
Keyword(s):  
Toxic Shock Syndrome ◽  
Group A Streptococcus ◽  
Streptococcal Toxic Shock Syndrome ◽  
Invasive Infection ◽  
Toxic Shock ◽  
Spherical Structures ◽  
Group A ◽  
Bacteria And Fungi

Streptococcus pyogenes (group A Streptococcus (GAS) is an important human pathogen that can cause severe invasive infection, such as necrotizing fasciitis and streptococcal toxic shock syndrome. The mortality rate of streptococcal toxic shock syndrome ranges from 20% to 50% in spite of antibiotics administration. AR-12, a pyrazole derivative, has been reported to inhibit the infection of viruses, intracellular bacteria, and fungi. In this report, we evaluated the bactericidal activities and mechanisms of AR-12 on GAS infection. Our in vitro results showed that AR-12 dose-dependently reduced the GAS growth, and 2.5 μg/mL of AR-12 significantly killed GAS within 2 h. AR-12 caused a remarkable reduction in nucleic acid and protein content of GAS. The expression of heat shock protein DnaK and streptococcal exotoxins was also inhibited by AR-12. Surveys of the GAS architecture by scanning electron microscopy revealed that AR-12-treated GAS displayed incomplete septa and micro-spherical structures protruding out of cell walls. Moreover, the combination of AR-12 and gentamicin had a synergistic antibacterial activity against GAS replication for both in vitro and in vivo infection. Taken together, these novel findings obtained in this study may provide a new therapeutic strategy for invasive GAS infection.

scholarly journals The scfCDE Operon Encodes a Predicted ABC Importer Required for Fitness and Virulence during Group A Streptococcus Invasive Infection

2019 ◽  
Vol 87 (12) ◽  
Author(s):  
Rezia Era Braza ◽  
Yoann Le Breton ◽  
Kevin S. McIver
Keyword(s):  
Soft Tissue ◽  
Group A Streptococcus ◽  
Defined Medium ◽  
Growth Defect ◽  
Invasive Infection ◽  
Competitive Growth ◽  
Content Type ◽  
Wide Range ◽  
Integral Role ◽  
Group A

ABSTRACT As a strict human pathogen, Streptococcus pyogenes (group A Streptococcus, or GAS) causes a wide range of infections, from superficial to life-threatening diseases, upon dissemination. Thus, it is necessary to gain a better understanding of how GAS successfully overcomes host-mediated challenges and infects various host niches. We previously identified subcutaneous fitness (scf) genes in the clinically relevant wild-type (WT) GAS M1T1 5448 strain that are critical for fitness during murine soft-tissue infection at both 24 h and 48 h postinfection. The uncharacterized locus scfCDE was transcribed as an operon and is predicted to encode an ABC importer for nutrient uptake (e.g., amino acids). Individual scfCDE deletion mutants grew comparably to WT 5448 in rich medium but exhibited reduced fitness during competitive growth in murine soft tissue and in nutrient-limiting chemically defined medium (CDM). A deletion of the permease gene scfD resulted in a monoculture growth defect in CDM that could be rescued by addition of excess peptides, suggesting a role as an amino acid importer. Interestingly, the ΔscfC substrate-binding and ΔscfD permease mutants, but not the ΔscfE ATPase mutant, were highly attenuated in murine soft tissue. Moreover, all three genes were required for GAS survival in human blood, indicating their impact is not limited to superficial infections. As such, scfCDE plays an integral role in enhancing GAS adaptation during localized infection as well as dissemination to deeper host environments. Since scfCDE is conserved throughout Firmicutes, this work may contribute to the development of therapeutic strategies against GAS and other Gram-positive pathogens.

scholarly journals CcpA-Mediated Repression of Streptolysin S Expression and Virulence in the Group A Streptococcus

2008 ◽  
Vol 76 (8) ◽  
pp. 3451-3463 ◽  
Author(s):  
Traci L. Kinkel ◽  
Kevin S. McIver
Keyword(s):  
Group A Streptococcus ◽  
Intraperitoneal Administration ◽  
Subcutaneous Administration ◽  
Sugar Metabolism ◽  
Virulence Gene ◽  
Systemic Infection ◽  
Lesion Size ◽  
Logarithmic Phase ◽  
Streptolysin S ◽  
Group A

ABSTRACT CcpA is the global mediator of carbon catabolite repression (CCR) in gram-positive bacteria, and growing evidence from several pathogens, including the group A streptococcus (GAS), suggests that CcpA plays an important role in virulence gene regulation. In this study, a deletion of ccpA in an invasive M1 GAS strain was used to test the contribution of CcpA to pathogenesis in mice. Surprisingly, the ΔccpA mutant exhibited a dramatic “hypervirulent” phenotype compared to the parental MGAS5005 strain, reflected as increased lethality in a model of systemic infection (intraperitoneal administration) and larger lesion size in a model of skin infection (subcutaneous administration). Expression of ccpA in trans from its native promoter was able to complement both phenotypes, suggesting that CcpA acts to repress virulence in GAS. To identify the CcpA-regulated gene(s) involved, a transcriptome analysis was performed on mid-logarithmic-phase cells grown in rich medium. CcpA was found to primarily repress 6% of the GAS genome (124 genes), including genes involved in sugar metabolism, transcriptional regulation, and virulence. Notably, the entire sag operon necessary for streptolysin S (SLS) production was under CcpA-mediated CCR, as was SLS hemolytic activity. Purified CcpA-His bound specifically to a cre within sagAp, demonstrating direct repression of the operon. Finally, SLS activity is required for the increased virulence of a ΔccpA mutant during systemic infection but did not affect virulence in a wild-type background. Thus, CcpA acts to repress SLS activity and virulence during systemic infection in mice, revealing an important link between carbon metabolism and GAS pathogenesis.

scholarly journals Regulation of capsule gene expression by group A Streptococcus during pharyngeal colonization and invasive infection

2008 ◽  
Vol 42 (1) ◽  
pp. 61-74 ◽  
Author(s):  
Ioannis Gryllos ◽  
Colette Cywes ◽  
Michael H. Shearer ◽  
Max Cary ◽  
Ronald C. Kennedy ◽  
...  
Keyword(s):  
Gene Expression ◽  
Group A Streptococcus ◽  
Invasive Infection ◽  
Group A

scholarly journals Metal sensing and regulation of adaptive responses to manganese limitation by MtsR is critical for group A streptococcus virulence

2019 ◽  
Vol 47 (14) ◽  
pp. 7476-7493 ◽  
Author(s):  
Hackwon Do ◽  
Nishanth Makthal ◽  
Pete Chandrangsu ◽  
Randall J Olsen ◽  
John D Helmann ◽  
...  
Keyword(s):  
Gene Regulation ◽  
Pathogenic Bacteria ◽  
Group A Streptococcus ◽  
Metal Availability ◽  
Invasive Infection ◽  
Adaptive Responses ◽  
Regulatory Activity ◽  
Group A ◽  
Metal Sensing ◽  
Fe Acquisition

Abstract Pathogenic bacteria encounter host-imposed manganese (Mn) limitation during infection. Herein we report that in the human pathogen Streptococcus pyogenes, the adaptive response to Mn limitation is controlled by a DtxR family metalloregulator, MtsR. Genes upregulated by MtsR during Mn limitation include Mn (mtsABC) and Fe acquisition systems (sia operon), and a metal-independent DNA synthesis enzyme (nrdFEI.2). To elucidate the mechanism of metal sensing and gene regulation by MtsR, we determined the crystal structure of MtsR. MtsR employs two Mn-sensing sites to monitor metal availability, and metal occupancy at each site influences MtsR regulatory activity. The site 1 acts as the primary Mn sensing site, and loss of metal at site 1 causes robust upregulation of mtsABC. The vacant site 2 causes partial induction of mtsABC, indicating that site 2 functions as secondary Mn sensing site. Furthermore, we show that the C-terminal FeoA domains of adjacent dimers participate in the oligomerization of MtsR on DNA, and multimerization is critical for MtsR regulatory activity. Finally, the mtsR mutant strains defective in metal sensing and oligomerization are attenuated for virulence in a mouse model of invasive infection, indicating that Mn sensing and gene regulation by MtsR are critical processes during S. pyogenes infection.

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