Acquisition of Complement Inhibitor Serine Protease Factor I and Its Cofactors C4b-Binding Protein and Factor H by Prevotella intermedia

Abstract

Infection with the Gram-negative pathogen Prevotella intermedia gives rise to periodontitis and a growing number of studies implies an association of P. intermedia with rheumatoid arthritis. The serine protease Factor I (FI) is the central inhibitor of complement degrading complement components C3b and C4b in the presence of cofactors such as C4b-binding protein (C4BP) and Factor H (FH). Yet, the significance of complement inhibitor acquisition in P. intermedia infection and FI binding by Gram-negative pathogens has not been addressed. Here we show that P. intermedia isolates bound purified FI as well as FI directly from heat-inactivated human serum. FI bound to bacteria retained its serine protease activity as shown in degradation experiments with 125 I-labeled C4b. Since FI requires cofactors for its activity we also investigated the binding of purified cofactors C4BP and FH and found acquisition of both proteins, which retained their activity in FI mediated degradation of C3b and C4b. We propose that FI binding by P. intermedia represents a new mechanism contributing to complement evasion by a Gram-negative bacterial pathogen associated with chronic diseases.

Periodontitis: from microbial immune subversion to systemic inflammation

“…Importantly, the bacterial proteases involved — namely, gingipains, karilysin and interpain A, expressed by P. gingivalis, T. forsythia and P. intermedia , respectively — act synergistically to inhibit complement, which may lead to enhanced protection of complement-susceptible bystander species 65-67 . P. intermedia and T. denticola can also evade human complement-mediated killing by capturing complement factor H, which is a physiological inhibitor of complement 68,69 .…”

Complement Involvement in Periodontitis: Molecular Mechanisms and Rational Therapeutic Approaches

“…For instance, P. gingivalis and Prevotella intermedia can capture and co-opt physiological soluble inhibitors of the complement cascade, such as the C4b-binding protein [88, 89] (Figure 3). In a similar context, T. denticola expresses an 11.4-kDa cell surface lipoprotein which binds complement factor H (hence known as factor H-binding protein) [90].…”

Role of complement in host–microbe homeostasis of the periodontium

“…Aggregatibacter actinomycetemcomitans uses its outer membrane protein 100 to bind the alternative pathway inhibitor factor H and acquire resistance to complement killing in serum [59]. P. intermedia binds the serine protease factor I (FI), a major inhibitor of complement that degrades C3b and C4b in the presence of cofactors such as C4BP and factor H [60]. Importantly, P. intermedia also binds the cofactors factor H and C4BP leading, respectively, to increased degradation of C4b and C3b [60].…”