Complement Evasion by Pathogenic Leptospira

Abstract

Leptospirosis is a neglected infectious disease caused by spirochetes from the genus Leptospira. Pathogenic microorganisms, notably those which reach the blood circulation such as Leptospira, have evolved multiple strategies to escape the host complement system, which is important for innate and acquired immunity. Leptospira avoid complement-mediated killing through: (i) recruitment of host complement regulators; (ii) acquisition of host proteases that cleave complement proteins on the bacterial surface; and, (iii) secretion of proteases that inactivate complement proteins in the Leptospira surroundings. The recruitment of host soluble complement regulatory proteins includes the acquisition of Factor H (FH) and FH-like-1 (alternative pathway), C4b-binding protein (C4BP) (classical and lectin pathways), and vitronectin (Vn) (terminal pathway). Once bound to the leptospiral surface, FH and C4BP retain cofactor activity of Factor I in the cleavage of C3b and C4b, respectively. Vn acquisition by leptospires may result in terminal pathway inhibition by blocking C9 polymerization. The second evasion mechanism lies in plasminogen (PLG) binding to the leptospiral surface. In the presence of host activators, PLG is converted to enzymatically active plasmin, which is able to degrade C3b, C4b, and C5 at the surface of the pathogen. A third strategy used by leptospires to escape from complement system is the active secretion of proteases. Pathogenic, but not saprophytic leptospires, are able to secrete metalloproteases that cleave C3 (central complement molecule), Factor B (alternative pathway), and C4 and C2 (classical and lectin pathways). The purpose of this review is to fully explore these complement evasion mechanisms, which act together to favor Leptospira survival and multiplication in the host.

Keywords: Leptospira; complement system; immune evasion; leptospirosis; serum resistance.

Figure 1

Complement evasion strategies of pathogenic Leptospira. To circumvent the complement system, Leptospira has evolved different immune evasion strategies: (i) acquisition of host soluble complement regulators: Factor H (FH)—AP regulator, C4b-binding protein (C4BP) —CP and LP regulator, and vitronectin (Vn) —terminal pathway regulator. FH and C4BP accelerate the decay of the C3 convertases (C3bBb and C4b2a, respectively) and act as cofactors for Factor I in C3b and C4b cleavages. Vn and the leptospiral protein LcpA bind C9 and inhibit its polymerization, thus potentially blocking MAC formation; (ii) acquisition of host proteases: pathogenic Leptospira binds plasminogen, which in the presence of activators, such as Urokinase-type plasminogen activator (uPA), is converted in the enzymatically active plasmin. This serine protease cleaves C3b, C4b, and C5, promoting a downregulation of complement activation on the Leptospira surface, and (iii) Direct inactivation of complement proteins by Leptospira endogenous proteases. Metalloproteases secreted by pathogenic Leptospira strains are able to cleave and inactivate the complement proteins: C3 (central complement molecule), Factor B (from AP), and C2 and C4 (CP and LP). Thermolysin is one of the proteases responsible for these cleavages, degrading C3. The combination of host-derived and endogenous factors from pathogenic Leptospira enables the bacteria to successfully establish infection and colonize target organs of the host.