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Infection and Immunity, December 2002, p. 6880-6890, Vol. 70, No. 12
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.12.6880-6890.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Opsonophagocytosis-Inhibiting Mac Protein of Group A Streptococcus: Identification and Characteristics of Two Genetic Complexes

Benfang Lei,1 Frank R. DeLeo,1 Sean D. Reid,1 Jovanka M. Voyich,1 Loranne Magoun,2 Mengyao Liu,1 Kevin R. Braughton,1 Stacy Ricklefs,1 Nancy P. Hoe,1 Robert L. Cole,1 John M. Leong,2 and James M. Musser1*

Laboratory of Human Bacterial Pathogenesis, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana 59840,1 Department of Molecular Genetics and Microbiology, University of Massachusetts Medical Center, Worcester, Massachusetts 016552

Received 29 May 2002/ Returned for modification 23 July 2002/ Accepted 7 August 2002

Recently, it was reported that a streptococcal Mac protein (designated Mac5005) made by serotype M1 group A Streptococcus (GAS) is a homologue of human CD11b that inhibits opsonophagocytosis and killing of GAS by human polymorphonuclear leukocytes (PMNs) (B. Lei, F. R. DeLeo, N. P. Hoe, M. R. Graham, S. M. Mackie, R. L. Cole, M. Liu, H. R. Hill, D. E. Low, M. J. Federle, J. R. Scott, and J. M. Musser, Nat. Med. 7:1298-1305, 2001). To study mac variation and expression of the Mac protein, the gene in 67 GAS strains representing 36 distinct M protein serotypes was sequenced. Two distinct genetic complexes were identified, and they were designated complex I and complex II. Mac variants in each of the two complexes were closely related, but complex I and complex II variants differed on average at 50.66 ± 5.8 amino acid residues, most of which were located in the middle one-third of the protein. Complex I Mac variants have greater homology with CD11b than complex II variants. GAS strains belonging to serotypes M1 and M3, the most abundant M protein serotypes responsible for human infections in many case series, have complex I Mac variants. The mac gene was cloned from representative strains assigned to complexes I and II, and the Mac proteins were purified to apparent homogeneity. Both Mac variants had immunoglobulin G (IgG)-endopeptidase activity. In contrast to Mac5005 (complex I), Mac8345 (complex II) underwent autooxidation of its cysteine residues, resulting in the loss of IgG-endopeptidase activity. A Mac5005 Cys94Ala site-specific mutant protein was unable to cleave IgG but retained the ability to inhibit IgG-mediated phagocytosis by human PMNs. Thus, the IgG-endopeptidase activity was not essential for the key biological function of Mac5005. Although Mac5005 and Mac8345 each have an Arg-Gly-Asp (RGD) motif, the proteins differed in their interactions with human integrins {alpha}vß3 and {alpha}IIbß3. Binding of Mac5005 to integrins {alpha}vß3 and {alpha}IIbß3 was mediated primarily by the RGD motif in Mac5005, whereas binding of Mac8345 involved the RGD motif and a region in the middle one-third of the molecule whose sequence is different in Mac8345 and Mac5005. Taken together, the data add to the emerging theme in GAS pathogenesis that allelic variation in virulence genes contributes to fundamental differences in host-pathogen interactions among strains.

* Corresponding author. Mailing address: Laboratory of Human Bacterial Pathogenesis, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 903 S. 4th Street, Hamilton, MT 59840. Phone: (406) 363-9315. Fax: (406) 363-9427. E-mail: jmusser{at}niaid.nih.gov.

Editor: D. L. Burns

Infection and Immunity, December 2002, p. 6880-6890, Vol. 70, No. 12
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.12.6880-6890.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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