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Partial loss of CovS function in Streptococcus pyogenes causes severe invasive disease.

ABSTRACT: BACKGROUND: CovRS (or CsrRS) is a two-component regulatory system that regulates the production of multiple virulence factors in Streptococcus pyogenes. covS mutations are often found in isolates recovered from mice that have been experimentally infected with S. pyogenes and covS mutations enhance bacterial virulence in an invasive infection mouse model. In addition, covS mutations were detected more frequently in a panel of clinical isolates from severe invasive streptococcal infections than those from non-severe infections. Thus, covS mutations may be associated with the onset of severe invasive infections. RESULTS: Known covS mutations were divided into two groups: (i) frameshift mutations that caused a deletion of functional regions and (ii) point mutations that caused single (or double) amino acid(s) substitutions. Frameshift mutations are frequent in mouse-passaged isolates, whereas point mutations are frequent in clinical isolates. The functions of CovS proteins with a single amino acid substitution in clinical isolates were estimated based on the streptococcal pyrogenic exotoxin B (SpeB) production and NAD+-glycohydrolase (NADase) activity, which are known to be regulated by the CovRS system. Point mutations partially, but not completely, impaired the function of the covS alleles. We also investigated some of the benefits that a partial loss of function in covS alleles with point mutations might confer on clinical isolates. We found that covS knockout mutants (?covS strains) had an impaired growth ability in a normal atmosphere in Todd Hewitt broth compared with parental isolates having wild-type or point-mutated covS. CONCLUSIONS: The loss of CovS proteins in S. pyogenes may confer greater virulence, but bacteria may also lose the ability to respond to certain external signals recognized by CovS. Therefore, point mutations that retain the function of CovS and confer hypervirulence may have natural selective advantages.

SUBMITTER: Tatsuno I

PROVIDER: S-EPMC3637574 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Partial loss of CovS function in Streptococcus pyogenes causes severe invasive disease.

Tatsuno Ichiro I Okada Ryo R Zhang Yan Y Isaka Masanori M Hasegawa Tadao T

BMC research notes 20130328

<h4>Background</h4>CovRS (or CsrRS) is a two-component regulatory system that regulates the production of multiple virulence factors in Streptococcus pyogenes. covS mutations are often found in isolates recovered from mice that have been experimentally infected with S. pyogenes and covS mutations enhance bacterial virulence in an invasive infection mouse model. In addition, covS mutations were detected more frequently in a panel of clinical isolates from severe invasive streptococcal infections ...[more]

PMID: 23537349

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Project description:Streptococcus pyogenes, also known as group A Streptococcus, causes a wide variety of diseases ranging from mild noninvasive to severe invasive infections. To identify possible causes of colonization-to-invasive switches, we determined the genomic sequences of 10 isolates from five pairs each composed of an invasive strain and a carriage strain originating from five infectious clusters. Among them, one pair displayed a single-nucleotide difference in covS, encoding the sensor histidine kinase of the two-component CovRS system that controls the expression of 15% of the genome. In contrast to previously described cases where the invasive strains harbor nonfunctional CovS proteins, the carriage strain possessed the mutation covST115C, leading to the replacement of the tyrosine at position 39 by a histidine. The CovSY39H mutation affected the expression of the genes from the CovR regulon in a unique fashion. Genes usually overexpressed in covS mutant strains were underexpressed and vice versa. Furthermore, the covS mutant strain barely responded to the addition of the CovS-signaling compounds Mg2+ and LL-37. The variations in the accumulation of two virulence factors paralleled the transcription modifications. In addition, the covST115C mutant strain showed less survival than its wild-type counterpart in murine macrophages. Finally, in two murine models of infection, the covS mutant strain was less virulent than the wild-type strain. Our study suggests that the CovSY39H protein compromises CovS phosphatase activity and that this yields a noninvasive strain. IMPORTANCE Streptococcus pyogenes, also known as group A Streptococcus, causes a wide variety of diseases, leading to 517,000 deaths yearly. The two-component CovRS system, which responds to MgCl2 and the antimicrobial peptide LL-37, controls the expression of 15% of the genome. Invasive strains may harbor nonfunctional CovS sensor proteins that lead to the derepression of most virulence genes. We isolated a colonization strain that harbors a novel covS mutation. This mutant strain harbored a transcriptome profile opposite that of other covS mutant strains, barely responded to environmental signals, and was less virulent than the wild-type strain. This supports the importance of the derepression of the expression of most virulence genes, via mutations that impact the phosphorylation of the regulator CovR, for favoring S. pyogenes invasive infections.

Project description:The gram-positive human pathogen Streptococcus pyogenes (group A streptococcus [GAS]) causes diseases ranging from mild and often self-limiting infections of the skin or throat to invasive and life-threatening illnesses. To cause such diverse types of disease, the GAS must be able to sense adverse environments and regulate its gene expression accordingly. The CovR/S two-component signal transduction regulatory system in GAS represses about 15% of the GAS genome, including many genes involved in virulence, in response to the environment. We report that CovR is still able to repress transcription from several promoters in the absence of the putative histidine kinase sensor for this system, CovS. We also show that a phosphorylation site mutant (D53A) of CovR is unable to repress gene expression. In addition, we report that a strain with a nonpolar mutation in CovS does not grow at a low pH, elevated temperature, or high osmolarity. The stress-related phenotypes of the CovS mutant were complemented by expression of covS from a plasmid. Selection for growth of a CovS mutant under stress conditions resulted in isolation of second-site mutations that inactivated covR, indicating that CovR and CovS act in the same pathway. Also, at 40 degrees C in the wild-type strain, CovR appeared to be less active on the promoter tested, which is consistent with the hypothesis that it was partially inactivated by CovS. We suggest that under mild stress conditions, CovS inactivates CovR, either directly or indirectly, and that this inactivation relieves repression of many GAS genes, including the genes needed for growth of GAS under stress conditions and some genes that are necessary for virulence. Growth of many gram-positive bacteria under multiple-stress conditions requires alteration of promoter recognition produced by RNA polymerase association with the general stress response sigma factor, sigma(B). We provide evidence that for GAS, which lacks a sigB ortholog, growth under stress conditions requires the CovR/S two-component regulatory system instead. This two-component system in GAS thus appears to perform a function for which other gram-positive bacteria utilize an alternative sigma factor.

Project description:BackgroundStreptococcus pyogenes is a major cause of severe, invasive infections in humans. The bacterial pathogen harbors a wide array of virulence factors and exhibits high genomic diversity. Rapid changes of circulating strains in a community are common. Understanding the current prevalence and dynamics of S. pyogenes lineages could inform vaccine development and disease control strategies.MethodsWe used whole-genome sequencing (WGS) to characterize all invasive S. pyogenes isolates obtained through the United States Center for Disease Control and Prevention's Active Bacterial Core surveillance (ABCs) in 2016 and 2017. We determined the distribution of strain features, including emm type, antibiotic resistance determinants, and selected virulence factors. Changes in strain feature distribution between years 2016 and 2017 were evaluated. Phylogenetic analysis was used to identify expanding lineages within emm type.ResultsSeventy-one emm types were identified from 3873 isolates characterized. The emm types targeted by a 30-valent M protein-based vaccine accounted for 3230 (89%) isolates. The relative frequencies of emm types collected during the 2 years were similar. While all isolates were penicillin-susceptible, erythromycin-resistant isolates increased from 273 (16% of 2016 isolates) to 432 (23% of 2017 isolates), mainly driven by increase of the erm-positive emm types 92 and 83. The prevalence of 24 virulence factors, including 11 streptococcal pyrogenic toxins, ranged from 6 to 90%. In each of three emm types (emm 49, 82, and 92), a subgroup of isolates significantly expanded between 2016 and 2017 compared to isolates outside of the subgroup (P-values < 0.0001). Specific genomic sequence changes were associated with these expanded lineages.ConclusionsWhile the overall population structure of invasive S. pyogenes isolates in the United States remained stable, some lineages, including several that were antibiotic-resistant, increased between 2016 and 2017. Continued genomic surveillance can help monitor and characterize bacterial features associated with emerging strains from invasive infections.

Project description:Necrotizing fasciitis is a severe infectious disease that results in significant mortality. Streptococcus pyogenes (group A Streptococcus, GAS) is one of the most common bacterial pathogens of monomicrobial necrotizing fasciitis. The early diagnosis of necrotizing fasciitis is crucial; however, the typical cutaneous manifestations are not always presented in patients with GAS necrotizing fasciitis, which would lead to miss- or delayed diagnosis. GAS with spontaneous inactivating mutations in the CovR/CovS two-component regulatory system is significantly associated with destructive diseases such as necrotizing fasciitis and toxic shock syndrome; however, no specific marker has been used to identify these invasive clinical isolates. This study evaluated the sensitivity and specificity of using CovR/CovS-controlled phenotypes to identify CovR/CovS-inactivated isolates. Results showed that the increase of hyaluronic acid capsule production and streptolysin O expression were not consistently presented in CovS-inactivated clinical isolates. The repression of SpeB is the phenotype with 100% sensitivity of identifying in CovS-inactivated isolates among 61 clinical isolates. Nonetheless, this phenotype failed to distinguish RopB-inactivated isolates from CovS-inactivated isolates and cannot be utilized to identify CovR-inactivated mutant and RocA (Regulator of Cov)-inactivated isolates. In this study, we identified and verified that PepO, the endopeptidase which regulates SpeB expression through degrading SpeB-inducing quorum-sensing peptide, was a bacterial marker to identify isolates with defects in the CovR/CovS pathway. These results also inform the potential strategy of developing rapid detection methods to identify invasive GAS variants during infection. IMPORTANCE Necrotizing fasciitis is rapidly progressive and life-threatening; if the initial diagnosis is delayed, deep soft tissue infection can progress to massive tissue destruction and toxic shock syndrome. Group A Streptococcus (GAS) with inactivated mutations in the CovR/CovS two-component regulatory system are related to necrotizing fasciitis and toxic shock syndrome; however, no bacterial marker is available to identify these invasive clinical isolates. Inactivation of CovR/CovS resulted in the increased expression of endopeptidase PepO. Our study showed that the upregulation of PepO mediates a decrease in SpeB-inducing peptide (SIP) in the covR mutant, indicating that CovR/CovS modulates SIP-dependent quorum-sensing activity through PepO. Importantly, the sensitivity and specificity of utilizing PepO to identify clinical isolates with defects in the CovR/CovS pathway, including its upstream RocA regulator, were 100%. Our results suggest that identification of invasive GAS by PepO may be a strategy for preventing severe manifestation or poor prognosis after GAS infection.

Dataset Information

Partial loss of CovS function in Streptococcus pyogenes causes severe invasive disease.

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Partial loss of CovS function in Streptococcus pyogenes causes severe invasive disease.

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