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

J Immunol. 2017 Dec 1;199(11):3828-3839. doi: 10.4049/jimmunol.1700426. Epub 2017 Oct 30.

Abstract

Bacteria can cause life-threatening infections, such as pneumonia, meningitis, or sepsis. Antibiotic therapy is a mainstay of treatment, although antimicrobial resistance has drastically increased over the years. Unfortunately, safe and effective vaccines against most pathogens have not yet been approved, and thus developing alternative treatments is important. We analyzed the efficiency of factor H (FH)6-7/Fc, a novel antibacterial immunotherapeutic protein against the Gram-positive bacterium Streptococcus pyogenes This protein is composed of two domains of complement inhibitor human FH (FH complement control protein modules 6 and 7) that bind to S. pyogenes, linked to the Fc region of IgG (FH6-7/Fc). FH6-7/Fc has previously been shown to enhance complement-dependent killing of, and facilitate bacterial clearance in, animal models of the Gram-negative pathogens Haemophilus influenzae and Neisseria meningitidis We hypothesized that activation of complement by FH6-7/Fc on the surface of Gram-positive bacteria such as S. pyogenes will enable professional phagocytes to eliminate the pathogen. We found that FH6-7/Fc alleviated S. pyogenes-induced sepsis in a transgenic mouse model expressing human FH (S. pyogenes binds FH in a human-specific manner). Furthermore, FH6-7/Fc, which binds to protein H and selected M proteins, displaced FH from the bacterial surface, enhanced alternative pathway activation, and reduced bacterial blood burden by opsonophagocytosis in a C3-dependent manner in an ex vivo human whole-blood model. In conclusion, FH-Fc chimeric proteins could serve as adjunctive treatments against multidrug-resistant bacterial infections.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Anti-Bacterial Agents / therapeutic use
  • Cells, Cultured
  • Complement C3 / metabolism
  • Complement C3 Convertase, Alternative Pathway
  • Complement Factor H / genetics
  • Complement Factor H / therapeutic use*
  • Drug Resistance, Multiple
  • Humans
  • Immunotherapy / methods*
  • Mice
  • Mice, Transgenic
  • Phagocytosis
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / therapeutic use*
  • Sepsis / immunology
  • Sepsis / therapy*
  • Staphylococcal Vaccines / immunology*
  • Streptococcal Infections / immunology
  • Streptococcal Infections / therapy*
  • Streptococcus pyogenes / immunology*

Substances

  • Anti-Bacterial Agents
  • Complement C3
  • Recombinant Fusion Proteins
  • Staphylococcal Vaccines
  • Complement Factor H
  • Complement C3 Convertase, Alternative Pathway