Sex differences in a murine model of infective endocarditis

TL;DR

Male mice develop more severe heart infection than females, mirroring human patterns, due to differences in immune responses.

Contribution

A murine model reveals sex-specific immune responses and disease severity in infective endocarditis.

Findings

Male mice had higher bacterial loads and worse cardiac outcomes compared to females.

Females showed earlier and stronger macrophage recruitment, correlating with reduced infection severity.

Males exhibited elevated systemic inflammation with higher cytokine levels.

Abstract

Infective endocarditis (IE) is a highly lethal disease with a notable male predominance, yet the biological basis for this sex disparity remains unclear. We established a murine IE model in C57BL6 mice in which aortic valve injury was induced via wire-injury and followed by intravenous injection of Staphylococcus aureus. Infection was confirmed by blood and valve cultures, and cardiac function was evaluated by echocardiography. Systemic cytokine levels were measured, and immune cell infiltration in valve tissue was assessed by flow cytometry and immunofluorescence. In the murine model, IE was induced in 77/85 animals. Male mice exhibited significantly higher bacterial loads in blood and valves, greater valve cusp enlargement, increased ventricular volumes, and more frequent aortic regurgitation. Both sexes showed strong neutrophilic responses, but males had markedly elevated systemic IL-1α, IL-1β, IL-6, and TNF-α levels. Females demonstrated earlier and more robust recruitment of CD68⁺ and CD206⁺ macrophages, as well as Ly6G⁺ neutrophils, to the injured valve, correlating with reduced bacterial vegetations. This murine model mirrors the clinical sex disparity in IE: males develop more severe disease and systemic inflammation, while females benefit from a rapid, localized immune response. These findings provide a platform for dissecting molecular drivers of sex-specific susceptibility in IE.

The online version contains supplementary material available at 10.1007/s00395-025-01127-8.

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