Background:
Infective endocarditis (IE) is among the most prevalent pathogen-induced cardiovascular disease entities. While the incidence of IE has nearly doubled during the past two decades, treatment options remain restricted to antibiotics and surgical valve repair. Still, patients with IE suffer from high morbidity and mortality rates, highlighting the urgent need for new therapeutic strategies. Our understanding of systemic immune responses to IE is limited, and most pathophysiological insights described thus far are restricted to histological studies in rodents. Here, we enrolled patients with clinically confirmed infective endocarditis in a prospective, longitudinal, and multicenter immunophenotyping study to profile the systemic host response to IE. By reverse translational approaches, we subsequently confirm the fundamental role of T cells as master regulators of IE.
Methods:
We used clinical data and multiomics profiling, including single-cell RNA sequencing of circulating blood mononuclear cells, plasma proteomics, and flow cytometry of whole blood, to identify endocarditis-specific immune responses. In vitro assays of neutrophil activation along with the novel “vegetation-on-a-chip” assay were used to mechanistically validate IE-specific molecular targets. A translationally relevant murine endocarditis model was used to underline T cells as crucial modulators of IE-directed immune responses.
Results:
Comparing IE patients to both healthy controls and patients with non-cardiac bacterial infections, we detect the upregulation of endocarditis-specific circulating factors, including high plasma levels of complement factors and the expansion of T cell clusters in IE. Among these clusters, we reveal circulating T cell subsets characterized by a pro-inflammatory phenotype that upregulate IE-specific transcriptional programs with elevated cytokine expression. In vitro, we use a novel vegetation-on-a-chip assay to confirm that in an IE-like microenvironment, soluble T cell factors activate myeloid cells and facilitate bacterial clearance through neutrophil activation and enhanced ROS production. Finally, T cell depletion in a translationally relevant mouse model of Staphylococcus aureus-induced IE aggravates disease severity and mortality, highlighting T cells as master regulators of the myeloid response to bacterial IE.
Conclusions:
These data provide the first in-depth immune landscape of human IE and provide mechanistic evidence of an unexpectedly fundamental role of T cells in mounting the endocarditis-specific host defense by orchestrating neutrophil responses. Our study further provides the first comprehensive immune landscape of human IE, representing a crucial resource for the development of novel immunomodulatory treatment approaches in this insidious disease.
