Biological significance of IgA1 proteases in bacterial colonization and pathogenesis: critical evaluation of experimental evidence

Abstract

IgA1 protease activity, which allows bacteria to cleave human IgA1 in the hinge region, represents a striking example of convergent evolution of a specific property in bacteria. Although it has been known since 1979 that IgA1 protease is produced by the three leading causes of bacterial meningitis in addition to important urogenital pathogens and some members of the oropharyngeal flora, the exact role of this enzyme in bacterial pathogenesis is still incompletely understood owing to lack of a satisfactory animal model. Cleavage of IgA1 by these post‐proline endopeptidases efficiently separates the monomeric antigen‐binding fragments from the secondary effector functions of the IgA1 antibody molecule. Several in vivo and in vitro observations indicate that the enzymes are important for the ability of bacteria to colonize mucosal membranes in the presence of S‐IgA antibodies. Furthermore, the extensive cleavage of IgA sometimes observed in vivo, suggests that IgA1 protease activity results in a local functional IgA deficiency that may facilitate colonization of other microorganisms and the penetration of potential allergens. It has been hypothesized that IgA1 protease activity of Haemophilus influenzae, Neisseria meningitidis, and Streptococcus pneumoniae, under special immunological circumstances, allows these bacteria to take advantage of specific IgA1 antibodies in a strategy to evade other immune factors of the human body. The decisive factor is the balance between IgA antibodies against surface antigens of the respective bacteria and their IgA1 protease. Recent studies have shown that serine‐type IgA1 proteases of H. influenzae, meningococci, and gonococci belong to a family of proteins used by a diverse group of Gramnegative bacteria for colonization and invasion.

Delivery strategies to enhance oral vaccination against enteric infections

“…SIgA forms a critical part of the intestinal immune system both in protection from harmful pathogens and in homeostasis [91]. It is especially suited to its role in the intestinal immune system as SIgA is highly protease resistant [92]. SIgA exerts its functions in defence against pathogens by neutralizing bacterial toxins, blocking adhesion molecules expressed by pathogens and transporting antigens and pathogens out of the LP back into the gut lumen [93] (Fig.…”

Cleavage of IgGs by proteases associated with invasive diseases

“…[38][39][40] Also, a number of microorganisms express immunoglobulin-degrading proteases that have been implicated as virulence factors in aiding bacterial colonization. 8,41,42 Other examples of bacterial IgG-degrading proteases include Streptococcal SpeB that cleaves IgG in the upper hinge, 43,44 a Pseudomonas elastaselike enzyme, 45 Mirabilysin of Proteus mirabilis, 46 and Trepolisin of Treponema denticola.…”

“…Thus, when it was observed that a number of these pathogens expressed IgA-degrading proteases (without similar actions on IgG), it was postulated to be a potential defense strategy against host immune surveillance in the GI tract. 42 The preferred sites of cleavage of secretory IgAs by various microbial proteases have been localized specifically to the hinge region. 76 These investigators generated a number of positional variants and deletion mutants to define certain alterations that could confer protease resistance.…”

“…Mechanistically, it was speculated that IgA proteases could facilitate the establishment of a localized zone of immunodeficiency around the microbe, 42 and that Fab cleavage products, by retention of anti-microbial antigen binding capacity, could obstruct the access of intact IgAs to the bacterial surface. 79 Proteolysis of IgA by microbes that colonize the mucosal compartment may be analogous to the proposed loss of IgG effector functions mediated by IgG-degrading proteases in tissues.…”

FcαRI (CD89) Alleles Determine the Proinflammatory Potential of Serum IgA

“…The two human IgA subclasses, IgA1 and IgA2, differ by an additional 13-aa sequence with O-linked glycosylation sites in the hinge region of IgA1 (4). The lack of 13 aa in the hinge confers on IgA2 its resistance to digestion by the bacterial proteases produced by microorganisms such as Streptococcus mutans, Neisseria meningitidis, and Haemophilus influenzae and may be the rationale for the predominance of IgA2 in mucosal secretions (5).…”