Utilizing complement evasion strategies to design complement-based antibacterial immunotherapeutics: Lessons from the pathogenic Neisseriae

Abstract

Novel therapies are urgently needed to combat the global threat of multidrug-resistant pathogens. Complement forms an important arm of innate defenses against infections. In physiological conditions, complement activation is tightly controlled by soluble and membrane-associated complement inhibitors, but must be selectively activated on invading pathogens to facilitate microbial clearance. Many pathogens, including Neisseria gonorrhoeae and N. meningitidis, express glycans, including N-acetylneuraminic acid (Neu5Ac), that mimic host structures to evade host immunity. Neu5Ac is a negatively charged 9-cabon sugar that inhibits complement, in part by enhancing binding of the complement inhibitor factor H (FH) through C-terminal domains (19 and 20) on FH. Other microbes also bind FH, in most instances through FH domains 6 and 7 or 18-20. Here we describe two strategies to target complement activation on Neisseriae. First, microbial binding domains of FH were fused to IgG Fc to create FH18-20/Fc (binds gonococci) and FH6,7/Fc (binds meningococci). A point mutation in FH domain 19 eliminated hemolysis caused by unmodified FH18-20, but retained binding to gonococci. FH18-20/Fc and FH6,7/Fc mediated complement-dependent killing in vitro and showed efficacy in animal models of gonorrhea and meningococcal bacteremia, respectively. The second strategy utilized CMP-nonulosonate (CMP-NulO) analogs of sialic acid that were incorporated into LOS and prevented complement inhibition by physiologic CMP-Neu5Ac and resulted in attenuated gonococcal infection in mice. While studies to establish the safety of these agents are needed, enhancing complement activation on microbes may represent a promising strategy to treat antimicrobial resistant organisms.

Gonococcal lipooligosaccharide sialylation: virulence factor and target for novel immunotherapeutics

“…A polymorphism in FH domain 7 (402H) decreases the binding of FH to malondialdehydes that accumulates in drusen (Weismann et al 2011), the retinal lesions that characterize the dry form of age-related macular degeneration, thereby permitting relatively uninhibited alternative pathway activation and accelerated disease progression. Several microbes, including N. gonorrhoeae and N. meningitidis, mimic their human hosts and bind to FH to escape killing by complement (Blom, Hallstrom and Riesbeck 2009;Ram et al 2016). Not surprisingly, most microbes also interact with FH through the same domains that interact with host cells-domains 6 and 7, and/or domains 19 and 20.…”

Factor H–IgG Chimeric Proteins as a Therapeutic Approach against the Gram-Positive Bacterial PathogenStreptococcus pyogenes

“…Further work is needed to delineate the exact mechanism of action of FH6-7/Fc on gram positive bacteria. Taken together, the FH6-7/hFc mediates opsonophagocytosis through 2 mechanisms: i) activating complement via C1q-IgG1 interaction and ii) blocking FH-dependent complement inhibition (see Fig 2 in (26)).…”

“…Similar to at least 10 other bacterial species (26), most strains of S. pyogenes recruit serum FH through domains 6 and 7 to their surface in order to protect themselves from complement attack (53, 54). The regions in FH that interact with microbes (domains 5–7 and 19–20) are distinct from the domains responsible for complement inhibition (domains 1–4).…”

“…However, bacteria ‘hijack’ these C4BP and FH to their surface (23) to escape opsonization and persist in the host (24). For example, several bacteria including S. pyogenes (25) bind FH via domains 6–7 or 18–20 (reviewed in(26)). Since the complement inhibiting activity of FH is located in domains 1–4, FH bound to surfaces via domains 6–7 or 18–20 can effectively limit complement activation (27).…”

Catch Me if You Can: <b><i>Streptococcus pyogenes</i></b> Complement Evasion Strategies

“…Interestingly, Scl1 binds FH via the conserved C-terminal domains 18–20, while all other FH-binding proteins recruit FH via the more N-terminal domains 5–7 [27]. The protective effect for complement evasion is mediated through FH and FHL1 or CFHR1, similar to the M protein family.…”