The Lectin Pathway of Complement Activation Is a Critical Component of the Innate Immune Response to Pneumococcal Infection

Abstract

The complement system plays a key role in host defense against pneumococcal infection. Three different pathways, the classical, alternative and lectin pathways, mediate complement activation. While there is limited information available on the roles of the classical and the alternative activation pathways of complement in fighting streptococcal infection, little is known about the role of the lectin pathway, mainly due to the lack of appropriate experimental models of lectin pathway deficiency. We have recently established a mouse strain deficient of the lectin pathway effector enzyme mannan-binding lectin associated serine protease-2 (MASP-2) and shown that this mouse strain is unable to form the lectin pathway specific C3 and C5 convertases. Here we report that MASP-2 deficient mice (which can still activate complement via the classical pathway and the alternative pathway) are highly susceptible to pneumococcal infection and fail to opsonize Streptococcus pneumoniae in the none-immune host. This defect in complement opsonisation severely compromises pathogen clearance in the lectin pathway deficient host. Using sera from mice and humans with defined complement deficiencies, we demonstrate that mouse ficolin A, human L-ficolin, and collectin 11 in both species, but not mannan-binding lectin (MBL), are the pattern recognition molecules that drive lectin pathway activation on the surface of S. pneumoniae . We further show that pneumococcal opsonisation via the lectin pathway can proceed in the absence of C4. This study corroborates the essential function of MASP-2 in the lectin pathway and highlights the importance of MBL-independent lectin pathway activation in the host defense against pneumococci.

The Group B Streptococcus–Secreted Protein CIP Interacts with C4, Preventing C3b Deposition via the Lectin and Classical Complement Pathways

“…We concluded that, in absence of specific Abs, CIP could interfere with LP complement amplification. Interestingly, Ali et al (38) recently demonstrated that the LP L-ficolin is also a critical component of the innate immune response to pneumococcal infection.…”

Low-dose recombinant properdin provides substantial protection againstStreptococcus pneumoniaeandNeisseria meningitidisinfection

“…Whereas N. meningitidis is susceptible mainly to terminal pathway-mediated lysis (11). S. pneumoniae is resistant to complement lysis but is usually cleared by phagocytosis after complement-mediated opsonization (8).…”

“…The complement system plays a major role in the host resistance to both pathogens (8)(9)(10)(11)(12)(13). Complement is activated via three routes: the classical pathway, the lectin pathway, and the alternative pathway.…”

“…Deposition of C3b and iC3b on the bacterial surface is a key step in the immune response against S. pneumoniae, because complement-mediated opsonisation is essential for clearance of S. pneumoniae through phagocytosis (8). Lysis of bacteria, owing to formation of the membrane attack complex complex, is the critically important biological activity of complement in the defense against N. meningitidis (10).…”

Ficolins do not alter host immune responses to lipopolysaccharide-induced inflammation in vivo

“…Lipopolysaccharide (LPS) from the outer membrane of Gram-negative bacteria plays a major role in activating the inflammatory response during sepsis, and administration of LPS in animal models has been widely used to study the inflammatory response to Gram-negative bacteria 26 . While a protective effect of ficolins has been demonstrated in clinical studies [27][28][29] and in mouse models of infection 13,[30][31][32] , the contribution of ficolins to inflammatory processes is not well-characterized. However, we recently observed that ficolin deficient mice showed decreased production of pro-inflammatory cytokines during local fungal lung infection in vivo 33 .…”