Key result
CXCR3 knockout protects against pneumococcal infection-induced heart failure driven by cardiac T-cell infiltration.
Why the study?
Severe Streptococcus pneumoniae infection increases the risk of post-infection heart failure through unresolved inflammation, but the specific cardiac transcriptomic response to acute bacterial infection and how it differs from acute sterile injury such as myocardial infarction required better characterization.
Does the CXCL10/CXCR3 axis drive the development of post-pneumonia heart failure in a mouse model of invasive Streptococcus pneumoniae infection?
Does the CXCL10/CXCR3 axis drive the development of post-pneumonia heart failure in a mouse model of invasive Streptococcus pneumoniae infection?
This preclinical study provides the first single-nucleus RNA sequencing atlas of a mouse heart during acute bacterial infection, identifying the CXCL9/10-CXCR3 axis and T-cell infiltration as key drivers of post-pneumonia heart failure.
Answers are grounded in this paper and cite their sources.
May warrant post-discharge cardiac monitoring after severe pneumococcal pneumonia; hypothesis-generating for targeting persistent inflammation to reduce long-term MACE.
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.
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Minassian et al. (2026) studied Post-pneumonia heart failure following acute Streptococcus pneumoniae infection. Acute Streptococcus pneumoniae infection and CXCR3/RAG1 knockout vs. Antibiotic-treated controls and 1-day post-myocardial infarction mouse hearts was evaluated on Transcriptomic profile (CXCL9/10 upregulation), cardiac CXCR3+ cell infiltration, and post-infection heart failure by echocardiography. Streptococcus pneumoniae infection uniquely upregulated cardiac CXCL9/10 at 24 hours with peak CXCR3+ T-cell infiltration at 8 days, while CXCR3 knockout protected mice from heart failure.
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