CXCR3 promotes development of heart failure following severe pneumococcal disease 2625

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Abstract Description Severe infection with Streptococcus pneumoniae (Spn), the leading cause of community-acquired pneumonia (CAP), is a significant long-term risk factor for major adverse cardiac events (MACE) such as heart failure (HF). Pulmonary and vascular inflammation is known to persist after CAP, despite treatment, suggesting that unresolved inflammation may be responsible for the increased risk of MACE in pneumonia survivors. To examine the role of inflammation in post-Spn HF and MACE, we utilized a well-established mouse model of invasive pneumococcal disease with antibiotic rescue. At 3 weeks post infection, rescued mice had reduced cardiac function as determined by echocardiography and increased inflammation relative to uninfected controls as determined by flow cytometry. Addition of hydrocortisone to antibiotic therapy reduced inflammation and prevented HF development. RAG1 KO mice were also protected from HF, suggesting inflammation mediates the development of HF post-Spn infection. Analysis of sera from patients hospitalized with Spn infection revealed increased markers of HF, such as BNP, and inflammation, such as CXCL9/10. Single nucleus RNA sequencing on hearts from infected mice demonstrated robust upregulation of CXCR3 ligands CXCL9/10 relative to uninfected controls. Mice lacking CXCR3 were protected from post-infection HF indicating CXCR3 mediates HF post-Spn infection. These results suggest immunomodulation should be further explored to prevent MACE in patients with CAP. Funding Sources Supported by NIH R01HL171136; NIH R01AI114800; NIH R21AI176193; UAB AMC21 Award; NIH T32AR069516; NIH T32GM008361. Topic Categories Cytokines and Chemokines and Their Receptors (CCR)

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