Clinical and immunological signatures of severe COVID-19 in previously healthy patients with clonal hematopoiesis

Identifying additional risk factors for COVID-19 severity in numerous previously healthy patients without canonical clinical risk factors remains challenging. In this study, we investigate whether clonal hematopoiesis of indeterminate potential (CHIP), a common aging-related process that predisposes various inflammatory responses, may exert COVID-19 severity. We examine the clinical impact of CHIP in 143 laboratory-confirmed COVID-19 patients. Both stratified analyses and logistic regression including the interaction between canonical risk factors and CHIP show that CHIP is an independent risk factor for severe COVID-19, especially in previously healthy patients. Analyses of 60,310 single-cell immune transcriptome profiles identify distinct immunological signatures for CHIP (+) severe COVID-19 patients, particularly in classical monocytes, with a marked increase in pro-inflammatory cytokine responses and potent IFN-{gamma} mediated hyperinflammation signature. We further demonstrate that the enhanced expression of CHIP (+) specific IFN-{gamma} response genes is attributed to the CHIP mutation-dependent epigenetic reprogramming of poised or bivalent cis-regulatory elements. Our results highlight a unique immunopathogenic mechanism of CHIP in the progression of severe COVID-19, which could be extended to elucidate how CHIP contributes to a variety of human infectious diseases.

Inflammation induces two types of inflammatory dendritic cells in inflamed lymph nodes

The spatiotemporal regulation of immune cells in lymph nodes (LNs) is crucial for mounting protective T-cell responses, which are orchestrated by dendritic cells (DCs). However, it is unclear how the DC subsets are altered by the inflammatory milieu of LNs. Here, we show that the inflamed LNs of Listeria-infected mice are characterized by the clustering of neutrophils and monocytes and IFN-γ production. Significantly, the early inflammatory responses are coupled with the differentiation of not one, but two types of CD64⁺CD11c⁺MHCII⁺ inflammatory DCs. Through the assessment of chemokine receptor dependency, gene expression profiles, growth factor requirements and DC-specific lineage mapping, we herein unveil a novel inflammatory DC population (we termed ‘CD64⁺ cDCs’) that arises from conventional DCs (cDCs), distinguishable from CD64⁺ monocyte-derived DCs (moDCs) in inflamed LNs. We determined that Listeria-induced type I IFN is a critical inflammatory cue for the development of CD64⁺ cDCs but not CD64⁺ moDCs. Importantly, CD64⁺ cDCs displayed a higher potential to activate T cells than CD64⁺ moDCs, whereas the latter showed more robust expression of inflammatory genes. Although CD64⁺ and CD64− cDCs were able to cross-present soluble antigens at a high dose to CD8⁺ T cells, CD64⁺ cDCs concentrated and cross-presented a minute amount of soluble antigens delivered via CD64 (FcγRI) as immune complexes. These findings reveal the role of early inflammatory responses in driving the differentiation of two inflammatory DC subsets empowered with distinct competencies.