title: Factor H binds to the hypervariable region of many Streptococcus pyogenes M proteins but does not promote phagocytosis resistance or acute virulence.
abstract: Many pathogens express a surface protein that binds the human complement regulator factor H (FH), as first described for Streptococcus pyogenes and the antiphagocytic M6 protein. It is commonly assumed that FH recruited to an M protein enhances virulence by protecting the bacteria against complement deposition and phagocytosis, but the role of FH-binding in S. pyogenes pathogenesis has remained unclear and controversial. Here, we studied seven purified M proteins for ability to bind FH and found that FH binds to the M5, M6 and M18 proteins but not the M1, M3, M4 and M22 proteins. Extensive immunochemical analysis indicated that FH binds solely to the hypervariable region (HVR) of an M protein, suggesting that selection has favored the ability of certain HVRs to bind FH. These FH-binding HVRs could be studied as isolated polypeptides that retain ability to bind FH, implying that an FH-binding HVR represents a distinct ligand-binding domain. The isolated HVRs specifically interacted with FH among all human serum proteins, interacted with the same region in FH and showed species specificity, but exhibited little or no antigenic cross-reactivity. Although these findings suggested that FH recruited to an M protein promotes virulence, studies in transgenic mice did not demonstrate a role for bound FH during acute infection. Moreover, phagocytosis tests indicated that ability to bind FH is neither sufficient nor necessary for S. pyogenes to resist killing in whole human blood. While these data shed new light on the HVR of M proteins, they suggest that FH-binding may affect S. pyogenes virulence by mechanisms not assessed in currently used model systems.
authors: Medical Microbiology Section, Department of Laboratory Medicine, Medical Faculty, Lund University, Lund, Sweden.
authors: Mattias C U
authors: MC
authors: Gustafsson
authors: Jonas
authors: J
authors: Lannergård
authors: O Rickard
authors: OR
authors: Nilsson
authors: Bodil M
authors: BM
authors: Kristensen
authors: John E
authors: JE
authors: Olsen
authors: Claire L
authors: CL
authors: Harris
authors: Rafael L
authors: RL
authors: Ufret-Vincenty
authors: Margaretha
authors: M
authors: Stålhammar-Carlemalm
authors: Gunnar
authors: G
authors: Lindahl
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology* / Q000378:metabolism*; D001425:Bacterial Outer Membrane Proteins / Q000276:immunology* / Q000378:metabolism*; D001665:Binding Sites; D002352:Carrier Proteins / Q000276:immunology* / Q000378:metabolism*; D050716:Complement C4b-Binding Protein / Q000378:metabolism; D017242:Complement Factor H / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010587:Phagocytosis; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013045:Species Specificity; D013290:Streptococcal Infections / Q000276:immunology / Q000382:microbiology; D013297:Streptococcus pyogenes / Q000276:immunology* / Q000378:metabolism / Q000472:pathogenicity*
chemical_list: D000942:Antigens, Bacterial; D001425:Bacterial Outer Membrane Proteins; C055609:C4BPA protein, human; D002352:Carrier Proteins; D050716:Complement C4b-Binding Protein; C014689:streptococcal M protein; D017242:Complement Factor H
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