Open AccessA Factor H-Fc fusion protein increases complement-mediated opsonophagocytosis and killing of community associated methicillin-resistant Staphylococcus aureus
Author(s) -
Megan A. G. Sage,
Katelyn D. Cranmer,
Michele L. Semeraro,
Shelby Ma,
Elena Galkina,
Yan Zhou Tran,
Keith L. Wycoff,
Julia A. Sharp
Publication year - 2022
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0265774
Subject(s) - staphylococcus aureus , microbiology and biotechnology , antibody opsonization , complement system , innate immune system , immune system , fusion protein , staphylococcal infections , protein a , complement control protein , biology , factor h , complement receptor 1 , immunology , chemistry , antibody , phagocytosis , bacteria , opsonin , gene , biochemistry , recombinant dna , genetics
Staphylococcus aureus employs a multitude of immune-evasive tactics to circumvent host defenses including the complement system, a component of innate immunity central to controlling bacterial infections. With antibiotic resistance becoming increasingly common, there is a dire need for novel therapies. Previously, we have shown that S . aureus binds the complement regulator factor H (FH) via surface protein SdrE to inhibit complement. To address the need for novel therapeutics and take advantage of the FH:SdrE interaction, we examined the effect of a fusion protein comprised of the SdrE-interacting domain of FH coupled with IgG Fc on complement-mediated opsonophagocytosis and bacterial killing of community associated methicillin-resistant S . aureus . S . aureus bound significantly more FH-Fc compared to Fc-control proteins and FH-Fc competed with serum FH for S . aureus binding. FH-Fc treatment increased C3-fragment opsonization of S . aureus for both C3b and iC3b, and boosted generation of the anaphylatoxin C5a. In 5 and 10% serum, FH-Fc treatment significantly increased S . aureus killing by polymorphonuclear cells. This anti-staphylococcal effect was evident in 75% (3/4) of clinical isolates tested. This study demonstrates that FH-Fc fusion proteins have the potential to mitigate the protective effects of bound serum FH rendering S . aureus more vulnerable to the host immune system. Thus, we report the promise of virulence-factor-targeted fusion-proteins as an avenue for prospective anti-staphylococcal therapeutic development.