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

Immunobiology. 2016 Oct;221(10):1110-23. doi: 10.1016/j.imbio.2016.05.016. Epub 2016 Jun 1.


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.

Keywords: Complement; Factor H; Immunotherapeutics; Neisseria; Sialic acid.

Publication types

  • Review
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology*
  • Anti-Bacterial Agents / therapeutic use
  • Antigens, Bacterial / immunology
  • Bacteria / chemistry
  • Bacteria / immunology*
  • Bacteria / metabolism
  • Bacterial Infections / drug therapy
  • Bacterial Infections / immunology*
  • Bacterial Infections / microbiology
  • Complement Activation / drug effects*
  • Complement Activation / immunology*
  • Complement Factor H / genetics
  • Complement Factor H / immunology
  • Complement System Proteins / immunology*
  • Drug Design*
  • Host-Pathogen Interactions / drug effects
  • Host-Pathogen Interactions / immunology
  • Humans
  • Immunoglobulin Fc Fragments / genetics
  • Immunoglobulin Fc Fragments / immunology
  • Immunologic Factors / pharmacology*
  • Immunologic Factors / therapeutic use
  • Molecular Mimicry / immunology
  • Neisseria / immunology
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / immunology
  • Recombinant Fusion Proteins / pharmacology
  • Sialic Acids / immunology


  • Anti-Bacterial Agents
  • Antigens, Bacterial
  • Immunoglobulin Fc Fragments
  • Immunologic Factors
  • Recombinant Fusion Proteins
  • Sialic Acids
  • Complement Factor H
  • Complement System Proteins