bioRxiv Science⌕ Search
Home/Archive/bioRxiv

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.
View original source ↗Export metadata ↓

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.

Explore related subjects

immunologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

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

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Systemic TLR7 agonism moderates disease severity in acute DSS-induced colitis in mice

Toll-like receptor 7 (TLR7) is an endosomal sensor of single-stranded RNA, studied for its antiviral and pro-inflammatory functions. Its role in intestinal inflammation is undefined, and no approved or clinical-stage therapy for inflammatory bowel disease (IBD) engages this pathway. Here we report that systemic administration of the reference TLR7 agonist GS-9620 (vesatolimod) moderates disease severity in acute dextran sodium sulfate (DSS)-induced colitis in mice. GS-9620-treated mice lost less weight, had lower Disease Activity Index scores, and were protected from DSS-induced colon shortening. Immunophenotyping of the spleen showed reduced Th17 and Tr17 populations and an increased proportion of regulatory T cells. These findings indicate that pharmacological TLR7 agonism is not merely tolerated in the inflamed intestine but is associated with a shift of the systemic immune compartment toward a regulatory phenotype. The results identify TLR7 as a candidate disease-moderating target in IBD and motivate direct tests of causality, route and chronic-disease relevance.

immunology↗
bioRxiv2026

ATF3 Preserves Macrophage Cholesterol Homeostasis during Metabolic Stress

Background: Macrophages must coordinate immune activation with maintenance of cellular cholesterol homeostasis, yet the transcriptional mechanisms integrating these processes remain incompletely understood. Activating transcription factor 3 (ATF3) suppresses inflammatory and interferon responses and has been implicated in macrophage lipid metabolism, suggesting a role in coordinating immune and sterol-responsive transcriptional programs. Methods: Wild-type and ATF3-deficient bone marrow-derived macrophages were analyzed by bulk RNA sequencing following Toll-like receptor stimulation and under conditions of sterol loading or depletion. Cholesterol content, cytokine production, and sterol-responsive gene expression were quantified. Human metabolic dysfunction-associated steatotic liver disease (MASLD) datasets and Kupffer cell-specific ATF3 knockout mice were used to assess disease relevance in vivo. Results: ATF3 deficiency enhanced inflammatory and interferon-responsive transcriptional programs while suppressing a sterol-responsive gene module enriched for SREBP2 target genes. This phenotype was conserved across diverse Toll-like receptor stimuli and accompanied by persistent Ch25h upregulation. Despite exhibiting elevated cellular cholesterol, ATF3-deficient macrophages retained transcriptional responsiveness to sterol loading and depletion while demonstrating reduced induction of SREBP2-dependent genes across conditions. IFNAR blockade reduced interferon-responsive gene expression but did not normalize Ch25h or sterol-responsive gene expression. In contrast, CRISPR-mediated reduction of Ch25h partially restored sterol-responsive gene expression in inflammatory ATF3-deficient macrophages. In human MASLD, hepatic ATF3 expression positively correlated with disease severity. In mice, ATF3 was preferentially induced in Kupffer cells during metabolic stress, and Kupffer cell-specific deletion of ATF3 increased liver injury and Kupffer cell lipid accumulation. Conclusions: ATF3 supports sterol-responsive transcriptional programs while restraining inflammatory activation in macrophages. ATF3 loss results in elevated cellular cholesterol, impaired SREBP2-dependent gene expression, and persistent derepression of Ch25h, which contributes to but does not fully explain the sterol phenotype. These findings identify ATF3 as a coordinator of macrophage adaptation to inflammatory and metabolic stress and support a protective role for Kupffer cell ATF3 during metabolic liver disease.

immunology↗
bioRxiv2026

Circulating CD4 regulatory T cells are broadly preserved in Parkinson's disease despite altered HELIOS expression

Background Regulatory T cells (Tregs) are an important component of adaptive immune regulation and have been implicated in Parkinson's disease (PD), with previous studies suggesting altered Treg proportions, phenotype and, in some cases, function. However, existing studies have been limited by variable phenotyping approaches and a lack of detailed functional assessment. Given the growing interest in Tregs as potential therapies in PD, better understanding of their phenotype and function in the disease is important. Methods Circulating FOXP3+ Tregs were characterised in individuals with PD and age-matched healthy controls (HC) using a 24-colour spectral flow cytometry panel. Treg suppressive function was assessed by their ability to inhibit proliferation and cytokine production by polyclonally stimulated autologous T effector cells in vitro. Treg lineage stability was assessed by analysis of FOXP3 TSDR demethylation. Results The proportions and phenotypic characteristics of circulating CD4 Tregs were broadly similar between individuals with PD and HCs, as were Treg suppressive function and FOXP3 TSDR demethylation. However, naive CD4 Tregs from individuals with PD showed reduced HELIOS expression, with a similar but non-significant trend in FOXP3 expression. Reduced HELIOS expression was also observed in the CD8 naive Treg compartment. Conclusions Major quantitative or functional abnormalities in circulating Tregs do not appear to be a dominant feature PD. However, reduced HELIOS expression in naive Tregs suggests more subtle phenotypic alterations that warrant further investigation. The broadly preserved suppressive function is reassuring for therapeutic approaches aimed at increasing Treg numbers, although it will be important to establish that expanded Tregs retain a stable phenotype and suppressive function in inflammatory and tissue environments.

immunology↗