A Human Fibrinogen Variant with Impaired StaphylococcusAureus Binding Function Promotes Host Survival during Septicemia in Mice
| Autor: | Matthew J. Flick, Linda Huisman, Miranda Weggeman, Amanda Stang, Jaap Koopman, Oscar Negron |
|---|---|
| Rok vydání: | 2018 |
| Předmět: | |
| Zdroj: | Blood. 132:3775-3775 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2018-99-118491 |
| Popis: | Staphylococcus aureus is a common gram-positive bacterium that is a causative agent for a number of life-threatening diseases. The emergence of antibiotic resistant strains of S. aureus (i.e., methicillin and vancomycin resistant) emphasizes a renewed need to better understand host-pathogen interactions for defining novel strategies to combat infection. The coagulation factor fibrinogen is a major target of S. aureus virulence factors as numerous fibrinogen-binding proteins are produced by the bacterium. Our previous studies, using FibgΔ5 mice that express a fibrinogen mutant lacking the binding motif for clumping factor A (ClfA) indicated that binding to this site is a major mechanism of pathogen virulence during acute septicemia. Specifically, in vivo studies showed that FibγΔ5 mice have improved survival following S. aureus bacteremia suggesting that this interaction is critical for S. aureus virulence. To investigate a potential clinical translation of these findings, we utilized variants of fibrinogen γ', an alternatively sliced form of fibrinogen (comprising 8-15% of total plasma fibrinogen) that has structural similarities to fibrinogenγΔ5. Specifically, we analyzed human fibrinogen γ' heterodimer (hFib γ-γ') and recombinant fibrinogen γ' homodimer (rFib γ'-γ'). For bacteria under stationary phase growth conditions, ClfA mediated binding to immobilized fibrinogen whereas under exponential growth conditions binding to fibrinogen was largely independent of ClfA. Interestingly, hFib γ-γ' supported both ClfA dependent and independent binding to fibrinogen. However, studies performed with rFib γ'-γ' showed that this variant almost completely abolished ClfA dependent and independent binding to fibrinogen. Similar results were observed in analyses of fibrinogen-dependent 'clumping' in solution. Fibrinogen-dependent 'clumping' was fully dependent on ClfA in both stationary and exponentially growing S. aureus. Importantly, reconstitution of fibrinogen-deficient mice or WT mice with hFibγ' provided a significant prolongation in host survival relative to mice reconstituted with hFibγ indicating that hFibγ' confers protection alone or when present with other fibrinogen species. These findings provide the proof-of-concept that naturally occurring fibrinogen variants could offer significant therapeutic potential against infection and potentially other diseases. Disclosures Koopman: Fibriant: Research Funding. Weggeman:Fibriant: Research Funding. Huisman:Fibriant: Research Funding. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|