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Published on: November 6, 2020
Fibrinogen γ' promotes host survival during Staphylococcus aureus septicemia in mice
Oscar Negrón1, Miranda Weggeman2, Jos Grimbergen2
1Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; UNC Blood Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
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 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.
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 FggΔ5 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 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.
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.
Insights
Human fibrinogen γ´-γ significantly improved survival in mice challenged with Staphylococcus aureus septicemia. This fibrinogen variant offers therapeutic potential against bacterial infections by reducing bacterial aggregation.
Area of Science:
- Infectious Diseases
- Hematology
- Microbiology
Background:
- Staphylococcus aureus causes sepsis by binding to host fibrinogen.
- A mutant fibrinogen (FggΔ5) lacking a binding motif improved survival in mice.
- Human fibrinogen γ´ is a splice variant that may lack S. aureus binding function.
Purpose of the Study:
- To determine if human fibrinogen γ´-γ provides host protection against S. aureus septicemia.
Main Methods:
- Survival and host response analyses in mice challenged with S. aureus.
- Mice were reconstituted with purified fibrinogen variants (phFibγ´-γ or phFibγ-γ) or were FggΔ5 mutants.
Main Results:
- Reconstitution with phFibγ´-γ significantly prolonged survival compared to phFibγ-γ and FggΔ5 mice.
- Improved survival was not due to altered adhesion or clumping, but smaller bacterial aggregates.
- Post-infection administration of phFibγ´-γ also improved survival.
Conclusions:
- Human fibrinogen γ´-γ demonstrates therapeutic potential against S. aureus septicemia.
- Modulating fibrinogen variant ratios could be a strategy for treating bacterial infections.
- This approach may also be applicable to other diseases.
