Abstract
The immune responses of males and females to bacterial infections display differences. The mechanisms that underlie this sexual dimorphism are multifactorial. Lipopolysaccharide (LPS) contributes to the pathogenesis of endotoxaemia. We have previously demonstrated that the plasma protein beta-2 glycoprotein-1 (β2GPI) reduces LPS-induced inflammation in male mice. In the present study using a more robust infection model of septicaemia the role of β2GPI is examined in both male and female wild type (WT) and β2GPI deficient (β2GPI−/−) mice challenged with Escherichia coli (E. coli) intravenously. β2GPI deficiency led to an increase of E. coli colony forming units (CFU) in the circulation of both male and female mice. In male β2GPI−/− mice this was associated with a worse clinical severity score. This difference was not observed between female β2GPI−/− and female WT mice. Male WT mice had decreased levels of total and increased levels of free thiol β2GPI following administration of LPS or E. coli. This pattern of sexual dimorphic response was also observed in our cohort of humans with sepsis. These findings support a role for β2GPI in modulating the sex-specific susceptibility to gram-negative septicaemia.
Highlights
Gram-negative bacterial infection in the blood leading to sepsis is an underestimated health risk and the main cause of death in hospital intensive care units (ICU) worldwide[1]
We present a role for β2GPI in controlling E. coli infection in the blood in both male and female mice and most strikingly we report on the differential influence of β2GPI on male and female septicaemia severity
Β2GPI did not influence the severity of septicaemia induced by intravenous administration of E. coli in female mice over 24 h
Summary
This is the first demonstration that the plasma protein β2GPI influences gram-negative septicaemia in a sex-specific manner following intravenous administration of live E. With E. coli had lower levels of plasma β2GPI compared to non-infected male mice challenged with pyrogen-free saline, whereas there was no change in total β2GPI levels in female mice challenged with E. coli or LPS compared to pyrogen free saline. To our knowledge this is the first report of a potential sex-specific plasma biomarker for gram negative septicaemia. We found an increase in the plasma of free thiol β2GPI generated in WT male mice in response to E. coli but not in female WT mice This sex-specific correlation in the levels of free thiol β2GPI was seen in male and female patients with sepsis. Our study delineates the role of β2GPI in murine septicaemia though not in murine sepsis, our preliminary patient data suggest that examining the role of β2GPI in sepsis models in the future is a reasonable avenue to pursue
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