Dataset Information

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.

SUBMITTER: Negron O

PROVIDER: S-EPMC10528022 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Publications

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

Negrón Oscar O Weggeman Miranda M Grimbergen Jos J Clark Emily G EG Abrahams Sara S Hur Woosuk S WS Koopman Jaap J Flick Matthew J MJ

Journal of thrombosis and haemostasis : JTH 20230330 8

<h4>Background</h4>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<sup>Δ5</sup> mice expressing mutant fibrinogen γ<sup>Δ5</sup> lacking a S. aureus binding motif had significantly improved survival following S. aureus septicemia. Fibrinogen γ' is a human splice varian ...[more]

PMID: 37001817

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Project description:A craniotomy is a neurosurgical procedure performed to access the intracranial space. In 3-5% of cases, infections can develop, most caused by Staphylococcus aureus biofilm formation on the skull surface. Medical management of this infection is difficult, as biofilm properties confer immune and antimicrobial recalcitrance to the infection and necessitate additional surgical procedures. Furthermore, treatment failure rates can be appreciably high. These factors, compounded with rapidly expanding rates of antimicrobial resistance, highlight the need to develop alternative treatment strategies to target and reverse the immune dysfunction that occurs during biofilm infection. Our recent work has identified CD4+ Th1 and Th17 cells as potent regulators of innate immune cell activation during craniotomy infection. Here, we report the role of IFN-γ, versus other Th1- and Th17-derived cytokines, in programing the immune response to biofilm infection using both global and cell type-specific IFN-γR1-deficient (Ifngr1-/-) mice. Bacterial burdens were significantly higher in Ifngr1-/- relative to WT animals despite few changes in immune cell abundance. Single-cell transcriptomics identified candidate explanations for this phenotype as alterations in cell death pathways, innate immune cell activation, MHC-II expression, and T cell responses were significantly reduced in Ifngr1-/- mice. While caspase-1 activation in PMNs and macrophage/microglial MHC-II expression were regulated by IFN-γ signaling, no phenotypes were observed with either granulocyte- or macrophage/microglia Ifngr1-/- conditional knockout mice, suggestive of redundancy. Instead, a decreased Th1/Th17 ratio was identified in Ifngr1-/- animals that was corroborated by elevated IL-17 levels and correlated with dysfunctional T cell-innate immune communication. Further, Th17 cells were less effective than Th1 cells in promoting S. aureus bactericidal activity in microglia and macrophages. Collectively, this work identifies a key protective role for IFN-γ during craniotomy infection by enhancing macrophage and microglial antibacterial activity. Therefore, controlled programming of IFN-γ responses may represent a novel therapeutic strategy for chronic craniotomy infections.

Dataset Information

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

Background

Objective

Methods

Results

Conclusion

Publications

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

Similar Datasets

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