https://doi.org/10.1007/s00392-025-02625-4
1Universitätsmedizin Greifswald Klinik und Poliklinik für Innere Medizin B Greifswald, Deutschland; 2Universität Greifswald Interfakultäres Institut für Genetik und Funktionelle Genomforschung - Abteilung Molekulare Genetik und Infektionsbiologie Greifswald, Deutschland; 3University Medicine Greifswald, Clinic for Internal Medicine B The partner site Greifswald of the German Center of Cardiovascular Research (DZHK) Greifswald, Deutschland
Introduction
Severe pneumonia is in up to 30% of patients associated with cardiac complications such as heart failure, arrhythmias, and myocardial infarctions. A number of risk factors are involved like older age, diabetes, septic shock or preexisting cardiac diseases. Another independent risk factor is an infection with Streptococcus pneumoniae. S. pneumoniae can cause high inflammatory host responses and is able to directly interact with the heart after translocation of the bacteria into the bloodstream. How the pneumococcus damages the heart and causes cardiomyopathy is not well understood, but pro-inflammatory cytokines, such as interleukin 1β (IL-1β) are implicated.
We have previously shown that activation of the NLRP3 inflammasome that is required for IL-1β activation and release contributes to the development of septic cardiomyopathy. If this plays a role in S. pneumoniae induced heart failure is not known.
Methods
In this study a mouse model of S. pneumoniae-induced heart failure was developed to test the hypothesis that S. pneumoniae infection leads to an activation of the NLRP3 inflammasome in the heart. 10-12-week female CD-1 mice were intranasally infected with S. pneumoniae TIGR4lux (6×107 bacteria, n=24) or PBS (n=15) for 72h. The progression of the infection was monitored every 12h using the IVIS® Spectrum Imaging System and blood cultures 72h post infection. Cardiac function was monitored by transthoracic echocardiography at 24h and 72h post infection. Changes in mRNA expression and protein contents of inflammasome components of the heart were quantitated by qRT-PCR and Western blot analysis, respectively. Heart morphology was analyzed using histological stainings.
Results
Infected mice show different courses of infection and outcomes with different times of detectable infection onset and severities from only slight infection to severe sepsis. Cardiac stress was induced in all infected animals with elevation Nppa and Nppb expression and an increased Myh7/Myh6 ratio independent on their infection status. Besides elevated proinflammatory markers like Il6, Socs3 and Tnfa on mRNA level, priming of the NLRP3 inflammasome in the heart was indicated by increased mRNA and protein expression of the NLRP3 inflammasome components IL-1β, NLRP3, caspase-1 and GSDMD in the heart. Accordingly, cleavage of caspase-1 and GSDMD indicating NLRP3 inflammasome activation occurred in the hearts of infected mice. This was accompanied by an infiltration of immune cells in the heart and changes in heart diameters.
Conclusion
Pneumococcal pneumonia is able to prime and activate the NLRP3 inflammasome in the heart. This activation may contribute to the development of cardiac complications during pneumococcal pneumonia. Further studies are needed to elucidate this pathway and to test if this can be used to prevent or treat cardiac complications during S. pneumoniae infection.