Utilizing complement evasion strategies to design complement-based antibacterial immunotherapeutics: Lessons from the pathogenic Neisseriae.
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.
Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, USA. Electronic address: sanjay.ram@umassmed.edu.
Sanjay
S
Ram
Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Jutamas
J
Shaughnessy
Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Rosane B
RB
DeOliveira
Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Lisa A
LA
Lewis
Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Sunita
S
Gulati
Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Peter A
PA
Rice
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000942:Antigens, Bacterial / Q000276:immunology; D001419:Bacteria / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D001424:Bacterial Infections / Q000188:drug therapy / Q000276:immunology* / Q000382:microbiology; D003167:Complement Activation / Q000187:drug effects* / Q000276:immunology*; D017242:Complement Factor H / Q000235:genetics / Q000276:immunology; D003165:Complement System Proteins / Q000276:immunology*; D015195:Drug Design; D054884:Host-Pathogen Interactions / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000276:immunology; D007155:Immunologic Factors / Q000494:pharmacology* / Q000627:therapeutic use; D018716:Molecular Mimicry / Q000276:immunology; D009343:Neisseria / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D012794:Sialic Acids / Q000276:immunology
D000900:Anti-Bacterial Agents; D000942:Antigens, Bacterial; D007141:Immunoglobulin Fc Fragments; D007155:Immunologic Factors; D011993:Recombinant Fusion Proteins; D012794:Sialic Acids; D017242:Complement Factor H; D003165:Complement System Proteins
Complement; Factor H; Immunotherapeutics; Neisseria; Sialic acid