Group A streptococcal SpeB modifies IgA through targeting regions other than the hingeVassen, Tanaka, Moll
et alMicrobiol Spectr (2025)
Abstract: Degradation of immunoglobulin (Ig) represents an important bacterial immune evasion strategy. For mucosal colonization, degradation of IgA is of particular importance, and many bacteria secrete specific IgA proteases that typically target the extended hinge region of IgA1. Such a specialized IgA protease has not yet been reported in Group A Streptococcus (GAS), despite its ability to successfully colonize human mucosal surfaces. In this study, we focused on the cysteine protease SpeB secreted by GAS and analyzed the interaction of SpeB with IgA. Assays using bacterial supernatants from wild-type and speB-deficient isogenic mutant strains, as well as recombinant SpeB, showed a SpeB-dependent IgA-modifying activity. SpeB resulted in the degradation of multimeric IgA, including the dimeric form, which was most notable in IgA2. The modification products were smaller in size than the heavy chain, suggesting a modification different from the classical hinge cleavage. Mass spectrometry analysis and glycosylation profiles indicated a putative cleavage in the C-terminal region, affecting the tailpiece and resulting in the loss of higher molecular weight multimeric/dimeric forms of IgA. Given the importance of dimeric IgA at mucosal surfaces, future studies are warranted to address whether IgA modification by SpeB represents a GAS immune evasion mechanism at this site.IMPORTANCEGroup A Streptococcus (GAS) is an important human pathogen with the ability to efficiently colonize mucosal surfaces and cause a wide spectrum of diseases ranging from pharyngotonsillitis to severe invasive infections or post-streptococcal sequelae. Immunoglobulins (Ig), in particular IgA, are critical effector molecules in the defense against pathogen colonization at mucosal surfaces. In this study, we focused on the cysteine protease SpeB, secreted by GAS, and investigated its interaction with human IgA. We report a SpeB-dependent IgA modification that involved the loss of multimeric/dimeric forms of IgA, predominantly affecting IgA2. The putative modification region is the C-terminus of IgA, which differs from the cleavage site of specialized IgA proteases targeting the hinge region. These findings suggest that IgA modification by SpeB might represent an immune evasion strategy utilized by GAS to colonize human mucosal tissue.
Development of the CRISPR-Cas12a-Based Biosensing System for Rapid, Ultrasensitive, and Highly Specific Detection of Streptococcus pyogenesJia, Zhang, Zhou
et alACS Omega (2025) 10 (9), 9768-9777
Abstract: Streptococcus pyogenes (group A streptococcus, GAS) is the leading bacterial cause of acute pharyngitis in children and adolescents. Rapid and reliable diagnosis of GAS pharyngitis is essential for guiding a timely antibiotic treatment. Here, we developed a rapid, highly sensitive, and specific test platform for the detection of GAS, designated GAS-MCDA-CRISPR. In this diagnostic platform, the multiple cross displacement amplification (MCDA) technique was utilized to preamplify the specific speB gene of GAS. Subsequently, the CRISPR-Cas12a-based biosensing system was employed to decode the MCDA products. MCDA primers, a guide RNA (gRNA), and a quenched fluorescent single-stranded DNA (ssDNA) reporter were designed to target the speB gene of GAS. The GAS-MCDA-CRISPR assay demonstrated the ability to detect GAS genomic DNA at a concentration as low as 45 fg per microliter while exhibiting no cross-reactivity with other non-GAS pathogens. Moreover, 56 clinical samples were correctly detected by the GAS-MCDA-CRISPR assay. These data highlighted that the GAS-MCDA-CRISPR assay is a reliable diagnostic tool for the reliable and quick diagnosis of GAS infection.© 2025 The Authors. Published by American Chemical Society.
Proinflammatory synergy between protease and superantigen streptococcal pyogenic exotoxinsJohnson, Bushman, LaRock
et alInfect Immun (2025) 93 (3), e0040524
Abstract: Streptococcal pyogenic exotoxins (Spe proteins) secreted by Streptococcus pyogenes (group A Streptococcus, GAS) are responsible for scarlet fever and streptococcal toxic shock syndrome. Most Spes are superantigens that cause excessive inflammation by activating large numbers of T cells. However, Streptococcal pyogenic exotoxin B (SpeB) is an exception, which is pro-inflammatory through its protease activity. Prior work shows that SpeB has the potential to cleave bacterial proteins. If cleavage of superantigens results in their inactivation, this gives the possibility that these two classes of exotoxins work at cross-purposes. We examined SpeB cleavage of the 11 major GAS superantigens and found that lability was not specific to structure, conservation, or, when compared to orthologous superantigens from Staphylococcus aureus, species of origin. We further show that rather than strictly antagonizing superantigen activity through degradation, SpeB can synergistically enhance superantigen-induced inflammation. For SpeB-labile superantigens, such as SmeZ, this is limited due to degradation, but for protease-resistant superantigens like SpeA, activity remains synergistic even at high protease concentrations. These findings suggest two modes by which proteases like SpeB may post-translationally regulate superantigens: positively, as a force amplifier that cooperatively increases inflammation, and negatively, through degradation that could act as a rheostat-like mechanism to limit excessive immune activation. Both mechanisms may contribute to the pathogenesis of GAS and other superantigen-producing pathogens.IMPORTANCEStreptococcus pyogenes produces both superantigen and protease virulence factors to subvert host immunity. However, its major protease is highly promiscuous and would potentially limit superantigen activity through its degradation. We profile the sensitivity of the streptococcal superantigens to degradation by the protease SpeB, providing evidence that many are highly resistant. Furthermore, we show that these important toxins can have synergistic proinflammatory activity. This provides insight into diseases like scarlet fever and toxic shock syndrome caused by these toxins and suggests anti-inflammatories that may be therapeutically useful.
Streptococcus pyogenes M1UK Variant-Associated Sartorius Muscle Necrotizing Soft Tissue Infection: A Case Report and Literature ReviewBaba, Ito, Ando
et alCureus (2024) 16 (12), e75765
Abstract: Necrotizing soft tissue infections (NTSIs) represent a concept of necrotizing infections involving the skin, subcutaneous tissue, fascia, and muscle, and it is a potentially fatal disease. Early exploratory incision is strongly recommended for both the diagnosis and treatment of necrotizing soft tissue infections. Treatment of necrotizing soft tissue infections requires the administration of appropriate antimicrobial agents and adequate surgical debridement. The emergence of M1UK-lineage Streptococcus pyogenes (S. pyogenes) is recently reported in the UK, Canada, the USA, and the Netherlands. We report a Japanese case of sartorius muscle (SM) NTSI caused by M1UK-lineage S. pyogenes. A 34-year-old man developed redness and swelling of his right thigh anterior compartment with fever in October 2024. The closed and deep effusions by active exploratory incision/debridement on hospital days one to three yielded the presence of Gram-positive cocci, although two sets of blood cultures upon admission revealed no bacterial growth; its species identification results indicated S. pyogenes. Clinical and pathological diagnosis was streptococcal SM NTSI (without toxic shock syndrome (TSS)). Negative pressure wound therapy with instillation and dwelling (NPWTi-d) to promote his soft tissue cure was performed along with antimicrobial regimens. The patient recovered and received micrografting (carrier: artificial dermis made from collagen sponge and silicon film, Pelnac Gplus® (Gunze Limited, Osaka, Japan) using the Rigenera® system (Rignera HBW, Candiolo, Italy). Thereafter, he developed bronchitis: the sputum yielded S. pyogenes growth: he recovered uneventfully. Split-thickness skin grafting (STG) was performed. Split-thickness skin grafting was fully engrafted, and the wounds achieved complete healing. The patient could walk by himself. Microbiological genetic analyses using both DNAs from effusion/sputum-origin strains revealed the emm1.0 and speA-speB-smeZ profiles. rofA-gldA-pstB sequencing results indicated M1UK-specific single-nucleotide polymorphisms. The streptococcal inhibitor of the complement-mediated lysis gene allele was the streptococcal inhibitor of the complement-mediated lysis-1.02 allele. Micrografting using the Rigenera® system and STG following NPWTi-d can be beneficial approaches. Clinicians should perform cultures using sterile specimens (deep effusions/tissues) from infection foci through exploratory incision/debridement, along with two sets of blood cultures, when examining patients with/without underlying medical conditions.Copyright © 2024, Baba et al.
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