Fibrinogen γ′ promotes host survival during Staphylococcus aureus septicemia in mice

Abstract

BackgroundStaphylococcus aureus is a common gram-positive bacterium that is the causative agent for several human diseases, including sepsis. A key virulence mechanism is pathogen binding to host fibrinogen through the C-terminal region of the γ-chain. Previous work demonstrated that FggΔ5 mice expressing mutant fibrinogen γΔ5 lacking a S. aureus binding motif had significantly improved survival following S. aureus septicemia. Fibrinogen γ′ is a human splice variant that represents about 10% to 15% of the total fibrinogen in plasma and circulates as a fibrinogen γ′-γ heterodimer (phFibγ′-γ). The fibrinogen γ′-chain is also expected to lack S. aureus binding function. ObjectiveDetermine if human fibrinogen γ′-γ confers host protection during S. aureus septicemia. MethodsAnalyses of survival and the host response following S. aureus septicemia challenge in FggΔ5 mice and mice reconstituted with purified phFibγ′-γ or phFibγ-γ. ResultsReconstitution of fibrinogen-deficient or wildtype mice with purified phFibγ′-γ prior to infection provided a significant prolongation in host survival relative to mice reconstituted with purified phFibγ-γ, which was superior to that observed with heterozygous FggΔ5 mice. Improved survival could not be accounted for by quantitative differences in fibrinogen-dependent adhesion or clumping, but phFibγ′-γ-containing mixtures generated notably smaller bacterial aggregates. Importantly, administration of phFibγ′-γ after infection also provided a therapeutic benefit by prolonging host survival relative to administration of phFibγ-γ. ConclusionThese findings provide the proof-of-concept that changing the ratio of naturally occurring fibrinogen variants in blood could offer significant therapeutic potential against bacterial infection and potentially other diseases.