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Factor H-IgG Chimeric Proteins as a Therapeutic Approach against the Gram-Positive Bacterial Pathogen Streptococcus pyogenes .
- Source :
-
Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2017 Dec 01; Vol. 199 (11), pp. 3828-3839. Date of Electronic Publication: 2017 Oct 30. - Publication Year :
- 2017
-
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.<br /> (Copyright © 2017 by The American Association of Immunologists, Inc.)
- Subjects :
- Animals
Anti-Bacterial Agents therapeutic use
Cells, Cultured
Complement C3 metabolism
Complement C3 Convertase, Alternative Pathway
Complement Factor H genetics
Drug Resistance, Multiple
Humans
Mice
Mice, Transgenic
Phagocytosis
Recombinant Fusion Proteins genetics
Sepsis immunology
Streptococcal Infections immunology
Complement Factor H therapeutic use
Immunotherapy methods
Recombinant Fusion Proteins therapeutic use
Sepsis therapy
Staphylococcal Vaccines immunology
Streptococcal Infections therapy
Streptococcus pyogenes immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1550-6606
- Volume :
- 199
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Publication Type :
- Academic Journal
- Accession number :
- 29084837
- Full Text :
- https://doi.org/10.4049/jimmunol.1700426