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Factor H–IgG chimeric proteins as a therapeutic approach against the gram-positive bacterial pathogen Streptococcus pyogenes

Blom, Anna M. LU ; Magda, Michal LU ; Kohl, Lisa; Shaughnessy, Jutamas; Lambris, John D.; Ram, Sanjay and Ermert, David LU (2017) In Journal of Immunology 199(11). p.3828-3839
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... (More)

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.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Immunology
volume
199
issue
11
pages
12 pages
publisher
American Association of Immunologists
external identifiers
  • scopus:85034774838
  • wos:000415967800014
ISSN
0022-1767
DOI
10.4049/jimmunol.1700426
language
English
LU publication?
yes
id
e7c95173-13b9-46fd-a335-5087953465db
date added to LUP
2017-12-07 13:30:34
date last changed
2018-07-15 04:45:59
@article{e7c95173-13b9-46fd-a335-5087953465db,
  abstract     = {<p>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.</p>},
  author       = {Blom, Anna M. and Magda, Michal and Kohl, Lisa and Shaughnessy, Jutamas and Lambris, John D. and Ram, Sanjay and Ermert, David},
  issn         = {0022-1767},
  language     = {eng},
  month        = {12},
  number       = {11},
  pages        = {3828--3839},
  publisher    = {American Association of Immunologists},
  series       = {Journal of Immunology},
  title        = {Factor H–IgG chimeric proteins as a therapeutic approach against the gram-positive bacterial pathogen Streptococcus pyogenes},
  url          = {http://dx.doi.org/10.4049/jimmunol.1700426},
  volume       = {199},
  year         = {2017},
}