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

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 alpha-subunit of Mac-1, a leukocyte beta2 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 (FcgammaRIIIB) 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.

In vivo enzymatic modulation of IgG glycosylation inhibits autoimmune disease in an IgG subclass-dependent manner

“…Besides EndoS, another enzyme (IdeS) from S. pyogenes was recently used successfully to interfere with autoantibody-induced tissue inflammation (28). In contrast to the modulation of the sugar moiety by EndoS, the protease IdeS is a cysteine endopeptidase that dissociates IgG it into one F(abЈ) 2 and two monomeric Fc fragments thereby uncoupling innate from adaptive immune responses (28)(29)(30). Despite the foreign nature and potential immunogenicity of these molecules, their use as first-line therapies should be very useful, and approaches aiming at a reduction of their immunogenicity will further increase their potential applicability in humans.…”

Leukocyte engagement of fibrin(ogen) via the integrin receptor αMβ2/Mac-1 is critical for host inflammatory response in vivo

“…These bacterial factors presumably serve a variety of purposes, but undoubtedly all are designed to increase the success of the microbe at the expense of the host, and many may have evolved as counter-measures to innate immune surveillance mechanisms. In addition to expressing the bacterial fibrinolytic agent, streptokinase, group A Streptococcus secrete a factor that is structurally similar to the α M subunit of α M β 2 , termed GAS-Mac, which increases bacterial virulence by inhibiting host phagocyte function (48). Similarly, S. aureus expresses an extraordinary array of factors designed to subvert the hemostatic system, including fibrinogen-binding proteins (e.g., ClfA), coagulase, and the fibrinolytic agent, staphlyokinase (49,50).…”

Blocking of experimental arthritis by cleavage of IgG antibodies in vivo

“…This extreme specificity not only contributes to the enzyme's lack of toxicity, but might also enhance its therapeutic effects; IgG autoantibodies usually are pathogenic, whereas IgM appears to suppress the development of autoimmune diseases (25). However, similar to the classic streptococcal cysteine proteinase streptococcal pyrogenic exotoxin B, IdeS contains an RGD motif (12,13), which is involved in the interaction of IdeS with vitronectin (␣V␤3) and platelet receptors (␣II␤3) (26) and likely confers other, as-yet-unknown, properties to the enzyme. To determine the specificity of IdeS activity in vivo in cleaving IgG2a antibodies and also to ascertain whether other properties of IdeS could account for its arthritis-inhibitory activity, we established 2 different CAIA models using IgG2a mAb (binding to CII epitopes J1 and C1 I ) and IgG2b mAb (binding to CII epitopes J1, D3, and U1) and administered IdeS treatment in both of these models.…”