Study of streptococcal hemoprotein receptor (Shr) in iron acquisition and virulence of M1T1 group A streptococcus.
Streptococcus pyogenes (group A streptococcus, GAS) is a human bacterial pathogen of global significance, causing severe invasive diseases associated with serious morbidity and mortality. To survive within the host and establish an infection, GAS requires essential nutrients, including iron. The streptococcal hemoprotein receptor (Shr) is a surface-localized GAS protein that binds heme-containing proteins and extracellular matrix components. In this study, we employ targeted allelic exchange mutagenesis to investigate the role of Shr in the pathogenesis of the globally disseminated serotype M1T1 GAS. The shr mutant exhibited a growth defect in iron-restricted medium supplemented with ferric chloride, but no significant differences were observed in neutrophil survival, antimicrobial peptide resistance, cell surface charge, fibronectin-binding or adherence to human epithelial cells and keratinocytes, compared with wild-type. However, the shr mutant displayed a reduction in human blood proliferation, laminin-binding capacity and was attenuated for virulence in in vivo models of skin and systemic infection. We conclude that Shr augments GAS adherence to laminin, an important extracellular matrix attachment component. Furthermore, Shr-mediated iron uptake contributes to GAS growth in human blood, and is required for full virulence of serotype M1T1 GAS in mouse models of invasive disease.
Department of Pediatrics, University of California San Diego, La Jolla, CA, USA.
Samira
S
Dahesh
Victor
V
Nizet
Jason N
JN
Cole
D000818:Animals; D016470:Bacteremia / Q000382:microbiology / Q000473:pathology; D002478:Cells, Cultured; D003470:Culture Media / Q000737:chemistry; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000382:microbiology; D005260:Female; D055786:Gene Knockout Techniques; D018390:Gene Targeting; D006420:Hemeproteins / Q000378:metabolism*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D015603:Keratinocytes / Q000382:microbiology; D051379:Mice; D050296:Microbial Viability; D009504:Neutrophils / Q000382:microbiology; D017192:Skin Diseases, Bacterial / Q000382:microbiology / Q000473:pathology; D013290:Streptococcal Infections / Q000382:microbiology / Q000473:pathology; D013297:Streptococcus pyogenes / Q000254:growth & development / Q000378:metabolism* / Q000472:pathogenicity*; D014774:Virulence; D037521:Virulence Factors / Q000378:metabolism*
D003470:Culture Media; D006420:Hemeproteins; D037521:Virulence Factors; D007501:Iron