Acute rheumatic fever (ARF) is a post-infectious complication of Streptococcus pyogenes, disproportionately affecting children in low- and middle-income settings. ARF causes diverse symptoms, with its most severe form leading to irreversible cardiac damage termed rheumatic heart disease (RHD). Despite its global burden, the molecular mechanisms of ARF remain elusive and no transcriptomic diagnostic biomarkers currently exist.
We investigated RNA signatures from whole blood transcriptomes of ARF in two distinct cohorts of children: Māori and Pacific from New Zealand (NZE) and Uganda. In the NZE cohort (n=39 cases; n=24 healthy controls), we explored how increasing severity of carditis affects gene expression whilst the Ugandan cohort expanded classifications to include definite ARF and various controls, including healthy individuals, those with endemic diseases and with RHD without acute ARF (n=45 cases; n=14 healthy controls; n=52 other controls). We identified 16 genes that were differentially expressed between ARF and healthy controls in both cohorts (e.g., DEFA4, log-fold change: 2.78 and 2.28, p-adjusted = 9.99 x 10-9 and 7.48 x 10-3 in the NZE and UG cohorts, respectively), as well as molecular markers specific for ARF-associated cardiac inflammation. Shared enriched pathways linked with ARF included neutrophil-driven inflammation and cardiotoxicity, providing insights into mechanisms of ARF.
Our results provide proof of principle that ARF has a distinct transcriptomic signature, regardless of country of origin, holding promise for RNA-based diagnostics to differentiate ARF from other inflammatory or infectious conditions. Ongoing efforts aim to integrate these findings into affordable diagnostic platforms to improve outcomes for vulnerable populations worldwide.