Single-cell transcriptome analyses reveal distinct gene expression signatures of severe COVID-19 in the presence of clonal hematopoiesis

COVID-19: Specific subgroup susceptible to severe disease An aging-related blood condition can trigger hyperinflammation across the body during COVID-19, enhancing the risk of severe disease. Clonal hematopoiesis of indeterminate potential (CHIP) occurs when stem cells begin making blood cells with a specific mutation, leading to groups of cells with a different genetic signature than the rest of the blood cells. CHIP can predispose people to particular inflammatory responses and even cancers. Inkyung Jung at the Korea Advanced Institute of Science and Technology, Daejeon, and co-workers demonstrated how CHIP can make people more susceptible to severe COVID-19 infection. The team analyzed samples from COVID-19 patients with and without CHIP at single-cell resolution. In those with CHIP, they identified a strong proinflammatory response in certain circulating white blood cells, which exacerbated systemic inflammation. Anti-inflammatory therapies that target these reponses may provide possible treatments. Clonal hematopoiesis of indeterminate potential (CHIP), a common aging-related process that predisposes individuals to various inflammatory responses, has been reported to be associated with COVID-19 severity. However, the immunological signature and the exact gene expression program by which the presence of CHIP exerts its clinical impact on COVID-19 remain to be elucidated. In this study, we generated a single-cell transcriptome landscape of severe COVID-19 according to the presence of CHIP using peripheral blood mononuclear cells. Patients with CHIP exhibited a potent IFN-gamma response in exacerbating inflammation, particularly in classical monocytes, compared to patients without CHIP. To dissect the regulatory mechanism of CHIP (+)-specific IFN-gamma response gene expression in severe COVID-19, we identified DNMT3A CHIP mutation-dependent differentially methylated regions (DMRs) and annotated their putative target genes based on long-range chromatin interactions. We revealed that CHIP mutant-driven hypo-DMRs at poised cis-regulatory elements appear to facilitate the CHIP (+)-specific IFN-gamma-mediated inflammatory immune response. Our results highlight that the presence of CHIP may increase the susceptibility to hyperinflammation through the reorganization of chromatin architecture, establishing a novel subgroup of severe COVID-19 patients.

Automated summary

A blood condition called CHIP, which is related to aging, can increase the susceptibility to severe COVID-19. Patients with CHIP showed a strong proinflammatory response in certain white blood cells, exacerbating systemic inflammation. Targeting these responses with anti-inflammatory therapies may offer potential treatments.