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

Abstract

Background: Staphylococcus 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 Fgg^Δ5 mice expressing mutant fibrinogen γ^Δ5 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.

Objective: Determine if human fibrinogen γ'-γ confers host protection during S. aureus septicemia.

Methods: Analyses of survival and the host response following S. aureus septicemia challenge in Fgg^Δ5 mice and mice reconstituted with purified phFibγ'-γ or phFibγ-γ.

Results: Reconstitution 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 Fgg^Δ5 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.

Conclusion: These 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.

Keywords: S. aureus; bacteremia; fibrinogen; sepsis.