Insight of host immune evasion mediated by two variants of group a Streptococcus Mac protein.
Group A Streptococcus has evolved numerous mechanisms to evade the host immune system to survive, disseminate, and cause disease. Recently a secreted protein named Mac-1 was identified and shown to enhance survival of the pathogen. A new variant of Mac-1 (designated Mac-2) also was recently described and shown to differ from Mac-1 by approximately 50% amino acid sequence divergence in the middle one-third of the molecule. To gain new information about the role of Mac-1 and Mac-2 in host-pathogen interactions, solution binding experiments were performed using surface plasmon resonance and purified Mac proteins. Mac-1 bound the same lower hinge region of human IgG as Fc receptors with 2.5 microM affinity, which lead to proteolytic cleavage of the antibody. Similar Km (6.8-18.9 microM) and kcat (0.02-0.13 s(-1)) values of the Mac-1 endopeptidase activity were obtained for IgG1, IgG2, IgG3, and IgG4. Mac-2 variant, in contrast, bound human IgG poorly (KD = 16 mM) and had weak endopeptidase activity against IgG. Instead, Mac-2 bound FcgammaRII and FcgammaRIII with 5 and 75 microM affinity, respectively. This binding competitively blocked IgG from recognition by Fc receptors. Taken together, Mac proteins block immunoglobulin recognition by Fc receptors and degrade immunoglobulins, thereby enhancing survival of the pathogen through the inhibition of phagocytosis, endocytosis of IgG-opsonized particles, and antibody-dependent cell-mediated cytotoxicity. Consequently, these proteins may be potential therapeutic targets.
Structural Immunology Section, Laboratory of Immunogenetics, NIAID, National Institutes of Health, Rockville, Maryland 20852, USA.
Johnson
J
Agniswamy
Benfang
B
Lei
James M
JM
Musser
Peter D
PD
Sun
D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000235:genetics* / Q000276:immunology*; D001665:Binding Sites; D005798:Genes, Bacterial; D014644:Genetic Variation; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000378:metabolism; D007074:Immunoglobulin G / Q000378:metabolism; D066298:In Vitro Techniques; D007700:Kinetics; D018448:Models, Immunological; D008969:Molecular Sequence Data; D011485:Protein Binding; D017452:Receptors, IgG / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013297:Streptococcus pyogenes / Q000235:genetics* / Q000276:immunology* / Q000472:pathogenicity
D001426:Bacterial Proteins; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; C442815:Mac-1-like protein, Streptococcus; D017452:Receptors, IgG