title: Serotype M3 and M28 Group A Streptococci Have Distinct Capacities to Evade Neutrophil and TNF-α Responses and to Invade Soft Tissues.
abstract: The M3 Serotype of Group A Streptococcus (GAS) is one of the three most frequent serotypes associated with severe invasive GAS infections, such as necrotizing fasciitis, in the United States and other industrialized countries. The basis for this association and hypervirulence of invasive serotype M3 GAS is not fully understood. In this study, the sequenced serotype M3 strain, MGAS315, and serotype M28 strain, MGAS6180, were characterized in parallel to determine whether contemporary M3 GAS has a higher capacity to invade soft tissues than M28 GAS. In subcutaneous infection, MGAS315 invaded almost the whole skin, inhibited neutrophil recruitment and TNF-α production, and was lethal in subcutaneous infection of mice, whereas MGAS6180 did not invade skin, induced robust neutrophil infiltration and TNF-α production, and failed to kill mice. In contrast to MGAS6180, MGAS315 had covS G1370T mutation. Either replacement of the covS1370T gene with wild-type covS in MGAS315 chromosome or in trans expression of wild-type covS in MGAS315 reduced expression of CovRS-controlled virulence genes hasA, spyCEP, and sse by >10 fold. MGAS315 covSwt lost the capacity to extensively invade skin and to inhibit neutrophil recruitment and had attenuated virulence, indicating that the covS G1370T mutation critically contribute to the hypervirulence of MGAS315. Under the background of functional CovRS, MGAS315 covSwt still caused greater lesions than MGAS6180, and, consistently under the background of covS deletion, MGAS6180 ΔcovS caused smaller lesions than MGAS315 ΔcovS. Thus, contemporary invasive M3 GAS has a higher capacity to evade neutrophil and TNF-α responses and to invade soft tissue than M28 GAS and that this skin-invading capacity of M3 GAS is maximized by natural CovRS mutations. These findings enhance our understanding of the basis for the frequent association of M3 GAS with necrotizing fasciitis.
authors.affiliation: Department of Microbiology and Immunology, Montana State University, Bozeman, Montana 59718, United States of America.
authors.forename: Zachary W
authors.initials: ZW
authors.lastname: Stetzner
authors.affiliation: Department of Microbiology and Immunology, Montana State University, Bozeman, Montana 59718, United States of America.
authors.forename: Dengfeng
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Microbiology and Immunology, Montana State University, Bozeman, Montana 59718, United States of America.
authors.forename: Wenchao
authors.initials: W
authors.lastname: Feng
authors.affiliation: Department of Microbiology and Immunology, Montana State University, Bozeman, Montana 59718, United States of America.
authors.forename: Mengyao
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Microbiology and Immunology, Montana State University, Bozeman, Montana 59718, United States of America.
authors.forename: Guanghui
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Microbiology and Immunology, Montana State University, Bozeman, Montana 59718, United States of America.
authors.forename: James
authors.initials: J
authors.lastname: Wiley
authors.affiliation: Department of Microbiology and Immunology, Montana State University, Bozeman, Montana 59718, United States of America.
authors.forename: Benfang
authors.initials: B
authors.lastname: Lei
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics; D016207:Cytokines / Q000378:metabolism; D005098:Exotoxins / Q000235:genetics; D005260:Female; D015964:Gene Expression Regulation, Bacterial; D000071677:Histidine Kinase; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D051379:Mice; D009154:Mutation; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000378:metabolism* / Q000382:microbiology; D010447:Peptide Hydrolases / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012703:Serotyping; D012867:Skin / Q000378:metabolism* / Q000382:microbiology; D013045:Species Specificity; D013290:Streptococcal Infections / Q000378:metabolism* / Q000382:microbiology; D013297:Streptococcus pyogenes / Q000145:classification / Q000235:genetics* / Q000472:pathogenicity; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D014774:Virulence / Q000235:genetics
chemical_list: D001426:Bacterial Proteins; C432143:CsrR protein, Streptococcus pyogenes; D016207:Cytokines; D005098:Exotoxins; D047908:Intracellular Signaling Peptides and Proteins; D012097:Repressor Proteins; C098249:RopB protein, Rhizobium leguminosarum; D014409:Tumor Necrosis Factor-alpha; C027951:erythrogenic toxin; C534547:CovS protein, Streptococcus pyogenes; D000071677:Histidine Kinase; D010447:Peptide Hydrolases; C527349:SpyCEP protein, Streptococcus pyogenes