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

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 & gamma;-chain. Previous work demonstrated that Fgg & UDelta;5 mice expressing mutant fibrinogen & gamma;& UDelta;5 lacking a S. aureus binding motif had significantly improved survival following S. aureus septicemia. Fibrinogen & gamma;& PRIME; is a human splice variant that represents about 10% to 15% of the total fibrinogen in plasma and circulates as a fibrinogen & gamma;& PRIME;-& gamma; heterodimer (phFib & gamma;& PRIME;-& gamma;). The fibrinogen & gamma;& PRIME;-chain is also expected to lack S. aureus binding function.Objective: Determine if human fibrinogen & gamma;& PRIME;-& gamma; confers host protection during S. aureus septicemia.Methods: Analyses of survival and the host response following S. aureus septicemia challenge in Fgg & UDelta;5 mice and mice reconstituted with purified phFib & gamma;& PRIME;-& gamma; or phFib & gamma;-& gamma;. Results: Reconstitution of fibrinogen-deficient or wildtype mice with purified phFib & gamma;& PRIME;-& gamma; prior to infection provided a significant prolongation in host survival relative to mice reconstituted with purified phFib & gamma;-& gamma;, which was superior to that observed with heterozygous Fgg & UDelta;5 mice. Improved survival could not be accounted for by quantitative differences in fibrinogen-dependent adhesion or clumping, but phFib & gamma;& PRIME;-& gamma;-containing mixtures generated notably smaller bacterial aggregates. Importantly, administration of phFib & gamma;& PRIME;-& gamma; after infection also provided a therapeutic benefit by prolonging host survival relative to administration of phFib & gamma;-& gamma;.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.