Protease-dependent mechanisms of complement evasion by bacterial pathogens

Abstract

The human immune system has evolved a variety of mechanisms for the primary task of neutralizing and eliminating microbial intruders. As the first line of defense, the complement system is responsible for rapid recognition and opsonization of bacteria, presentation to phagocytes and bacterial cell killing by direct lysis. All successful human pathogens have mechanisms of circumventing the antibacterial activity of the complement system and escaping this stage of the immune response. One of the ways in which pathogens achieve this is the deployment of proteases. Based on the increasing number of recent publications in this area, it appears that proteolytic inactivation of the antibacterial activities of the complement system is a common strategy of avoiding targeting by this arm of host innate immune defense. In this review, we focus on those bacteria that deploy proteases capable of degrading complement system components into non-functional fragments, thus impairing complement-dependent antibacterial activity and facilitating pathogen survival inside the host.

Figure 1

Biphasic effect of periodontal pathogens-derived proteases on the complement system. P. gingivalis gingipains, P. intermedia interpain A, and T. forsythia karilysin, when present at low concentrations (i.e. early in the colonization process or at a longer distance from the dental plaque) activate the C1 complex leading to deposition of C1q on the bacterial surface. Complement activation may eliminate complement-sensitive bacteria, which could otherwise compete with the pathogens for space and nutrients. At higher concentrations (i.e. in a developed biofilm) proteases supress the physiological activation of the complement cascade by sequential cleavage of C3, C4, and C5 components of complement. The very efficient initial cleavage releases anaphylatoxins and C4a. At the same time degradation of C3b, C4b, and C5b into non-functional fragments synergistically inhibits bactericidal activity of complement thus protecting complement-sensitive bacteria in their proximity and promoting biofilm development. The locally released anaphylatoxins fuel inflammation, resulting in tissue damage and nutrients generation, as well as they are subjugated for immune evasion paralyzing clearance of P. gingivalis by phagocytes (Guo et al., 2003; Huber-Lang et al., 2002; Riedemann et al., 2003). Targets for bacterial proteases are depicted by scissors.

Figure 2

Activation pathways of the complement system and points of bacterial proteases action. Complement cascade initiates through three major pathways. The classical one activates upon binding of antibodies to their corresponding antigens. It results in activation of serine proteases (C1s and C1r), cleavage of C4 and C2 and consecutive formation of C3 convertase (C4b2b). Binding of MBL to mannose residues on the surface of microorganisms activates the lectin pathway, via activation of mannan-binding lectin serine proteases (MASP), which then cleave C4 and C2, resulting in formation of C3 convertase (C4b2b). The alternative pathway starts due to failure to appropriately regulate constant low-level spontaneous deposition of activated C3 on foreign surfaces. Spontaneously hydrolyzed C3 binds factor B (FB), leading to formation of the initial alternative pathway C3 convertase (C3bBb). All three pathways converge at a central step, involving activation of C3, leading to the generation of the anaphylatoxin C3a and opsonins C3b and iC3b. In the terminal pathway, C5b initiates the assembly of the C5b–9 membrane-attack complex (MAC), which in turn stimulates microbial cell lysis. Targets for bacterial proteases are depicted by red scissors. C1inh, C1 inhibitor.