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Evasion of human innate and acquired immunity by a bacterial homolog of CD11b that inhibits opsonophagocytosis

Nature Medicine volume 7, pages 1298–1305 (2001)Cite this article

Abstract

Microbial pathogens must evade the human immune system to survive, disseminate and cause disease. By proteome analysis of the bacterium Group A Streptococcus (GAS), we identified a secreted protein with homology to the α-subunit of Mac-1, a leukocyte β2 integrin required for innate immunity to invading microbes. The GAS Mac-1–like protein (Mac) was secreted by most pathogenic strains, produced in log-phase and controlled by the covR-covS two-component gene regulatory system, which also regulates transcription of other GAS virulence factors. Patients with GAS infection had titers of antibody specific to Mac that correlated with the course of disease, demonstrating that Mac was produced in vivo. Mac bound to CD16 (FcγRIIIB) on the surface of human polymorphonuclear leukocytes and inhibited opsonophagocytosis and production of reactive oxygen species, which resulted in significantly decreased pathogen killing. Thus, by mimicking a host-cell receptor required for an innate immune response, the GAS Mac protein inhibits professional phagocyte function by a novel strategy that enhances pathogen survival, establishment of infection and dissemination.

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Figure 1: Homology of streptococcal Mac and human CD11b.
Figure 2: Mac production by GAS and analysis of Mac antibody titers in patients with GAS disease.
Figure 3: Mac-dependent inhibition of ROS production during phagocytosis.
Figure 4: Mac inhibits phagocytosis and killing of GAS by human PMNs.
Figure 5: Interaction of Mac with host cells and with CD16/Mac-1.
Figure 6: Model of how streptococcal Mac modulates human CD16/Mac-1 function.

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Acknowledgements

We thank R. Ingalls for providing the transfected CHO cell line expressing Mac-1; K. Hasenkrug and R. Messer for assistance with flow cytometry; and S. Falkow, K. Hasenkrug, R. M. Krause, J. Portis and I. Weissman for critical comments. This study was supported in part by Public Health Service grants AI20723 and T32AI07470.

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Author notes

  1. Benfang Lei and Frank R. DeLeo: B.L. and F.R.D. contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Human Bacterial Pathogenesis, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, Hamilton, Montana, USA

    Benfang Lei, Frank R. DeLeo, Nancy P. Hoe, Morag R. Graham, Stacy M. Mackie, Robert L. Cole, Mengyao Liu & James M. Musser

  2. Departments of Pathology, Pediatrics and Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA

    Harry R. Hill

  3. Department of Microbiology, Mount Sinai Hospital and University of Toronto, Ontario, Canada

    Donald E. Low

  4. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA

    Michael J. Federle & June R. Scott

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Correspondence to James M. Musser.

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Lei, B., DeLeo, F., Hoe, N. et al. Evasion of human innate and acquired immunity by a bacterial homolog of CD11b that inhibits opsonophagocytosis. Nat Med 7, 1298–1305 (2001). https://doi.org/10.1038/nm1201-1298

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