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bioRxiv · 10.1101/2022.12.07.519499

Neutrophil-driven cardiac damage during invasive Streptococcus pneumoniae infection is regulated by CD73

Bhalla, M.·Ravi, V. R.·Lenhard, A.·Tchalla, E. Y. I.·Lang, J. K.·Ghanem, E. N. B.
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Abstract

Streptococcus pneumoniae (pneumococcus)-induced cardiac events are one of the life-threatening infection outcomes of invasive pneumococcal disease. S. pneumoniae has the ability to invade the myocardium and damage cardiomyocytes, however the contribution of the immune response during this process is not fully understood. We previously found that polymorphonuclear cells (PMNs) are crucial for host defense against S. pneumoniae lung infection and that extracellular adenosine (EAD) production, by exonucleosidases CD39 and CD73, controlled the anti-bacterial functions of these cells. The objective of this study was to explore the role of PMNs and the EAD-pathway in host cardiac damage during invasive pneumococcal infection. Upon intra-peritoneal (i.p.) injection with invasive S. pneumoniae TIGR4 strain, hearts of C57BL/6 mice showed an increased influx of PMNs as determined by flow cytometry. However, the increased PMN numbers failed to contain the bacterial burden in the heart and showed positive correlation with serum levels of the cardiac damage marker Troponin-1. Influx of PMNs into the heart was associated with constant presence of neutrophil degranulation products in the cardiac tissue. Depletion of PMNs prior infection reduced pneumococcal burden in the heart and lowered the Troponin-1 levels thus, indicating their role in cardiac damage. While exploring the mechanisms underlying the damaging PMN response, we found that by 24hpi, there was a significant reduction in the expression of CD39 and CD73 on cardiac PMNs. The role of CD73 in regulating cardiac damage was tested in vivo using CD73-/- mice which had significantly higher bacterial burden and cardiac damage compared to wild type mice despite similar PMN numbers. The role of CD73 expression on PMNs was also tested ex vivo using the HL-1 cardiomyocyte cell line which upon S. pneumoniae infection, showed increased cell death in presence of CD73-/- PMNs. Our findings have identified a detrimental role for PMNs in cardiac damage during invasive pneumococcal infection that is in part driven by reduced expression of EAD-producing enzymes in late disease stages.

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Bhalla, M., Ravi, V. R., Lenhard, A., Tchalla, E. Y. I., Lang, J. K., Ghanem, E. N. B.. 2022-12-07. Neutrophil-driven cardiac damage during invasive Streptococcus pneumoniae infection is regulated by CD73. https://doi.org/10.1101/2022.12.07.519499

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