Comparative transcriptomics reveals CXCL10/CXCR3 axis as a key driver of post-pneumonia heart failure

Abstract

Severe infection with Streptococcus pneumoniae (Spn), a Gram-positive bacterium and the leading cause of community-acquired pneumonia (CAP), is a significant long-term risk factor for new or worsening major adverse cardiac events (MACE) such as heart failure (HF), myocardial infarction, and arrhythmia. Inflammation has increasingly been implicated as a risk factor for cardiovascular disease and pulmonary and vascular inflammation is known to persist after CAP suggesting that unresolved inflammation, despite successful treatment, may be responsible for the increased risk of MACE observed in pneumonia survivors. It was recently demonstrated in a well-established mouse model of invasive pneumococcal disease with antibiotic rescue that excess inflammation is tied to the development of post-infection heart failure, as addition of hydrocortisone to antibiotic therapy reduces inflammation and prevents HF development. To better understand the cardiac response to acute Spn infection and how it differs from the response to acute sterile injury such as MI, we performed single-nucleus RNA sequencing (snRNAseq) on mouse hearts ~24 hours post infection and antibiotic-treated control hearts. We compared the results with publicly available snRNAseq data from mouse hearts one day post myocardial infarction and sham controls. Comparative transcriptomics analysis identified robust and unique upregulation of the CXCR3 ligands CXCL9/10 in infected hearts, which was not identified in the infarction dataset. Flow cytometry analysis revealed a peak infiltration of CXCR3+ cells, which were primarily T cells, at 8 days post infection. RAG1 KO mice, which lack mature B cells and T cells, were partially protected from heart failure, as determined by echocardiography, whereas CXCR3 KO mice experienced even greater protection. Our results, to our knowledge, constitute the first snRNAseq atlas of a mouse heart during acute bacterial infection and suggest immunomodulation should be further explored to prevent MACE in patients with CAP.