Multi-omic profiling reveals widespread dysregulation of innate immunity and hematopoiesis in COVID-19

Abstract

Our understanding of protective vs. pathologic immune responses to SARS-CoV-2, the virus that causes Coronavirus disease 2019 (COVID-19), is limited by inadequate profiling of patients at the extremes of the disease severity spectrum. Here, we performed multi-omic single-cell immune profiling of 64 COVID-19 patients across the full range of disease severity, from outpatients with mild disease to fatal cases. Our transcriptomic, epigenomic, and proteomic analyses reveal widespread dysfunction of peripheral innate immunity in severe and fatal COVID-19, with the most profound disturbances including a prominent neutrophil hyperactivation signature and monocytes with anti-inflammatory features. We further demonstrate that emergency myelopoiesis is a prominent feature of fatal COVID-19. Collectively, our results reveal disease severity-associated immune phenotypes in COVID-19 and identify pathogenesis-associated pathways that are potential targets for therapeutic intervention.One Sentence SummarySingle-cell profiling demonstrates multifarious dysregulation of innate immune phenotype associated with COVID-19 severity.

Neutrophils and COVID-19: Active Participants and Rational Therapeutic Targets

“…This enrichment in neutrophil signatures has been shown to be independent of lung injury, age, gender and underlying co-morbidities (78), suggesting that rather than simply representing a marker of severe lung inflammation, neutrophils contribute to the immunopathology that underpins the onset of COVID-19 pneumonia (78). Akin to the findings reported in whole blood (17,18,21), heterogeneity has also been reported in the pulmonary neutrophil pool (48,78). Wauters et al clustered BALF residing neutrophils into five distinct phenotypes and found the frequency of both "progenitor" and "inflammatory mature" neutrophils were significantly higher in samples from mild/critical COVID-19 patients when compared to subjects with non-COVID-19 pneumonia (78).…”

“…Using a range of analytical approaches that have included single cell RNA-seq (scRNA-seq), high-dimensional flow cytometry and mass cytometry, a number of studies have reported marked differences in the composition of the circulating neutrophil pool between COVID-19 patients of differing disease severities (18,29,48,49,(122)(123)(124)(125). Supporting the idea that distinct innate immune responses underlie the different clinical trajectories of COVID-19, an accumulation of LDNs is emerging as a signature of severe disease (18,21).…”

“…However, as adults aged 20-44 years account for 20% and 12% of COVID-19-associated hospitalisations and ICU admissions respectively (13), and >5% of hospitalised younger adults (aged 18-34 years) with no underlying health conditions experience respiratory failure (14), additional host and/or virus-associated factors must contribute to disease pathogenesis. A dysregulated physiological response to SARS-CoV-2 infection is one such factor, with striking differences observed in the immune response of COVID-19 patients when graded by disease severity, with a profound inflammatory and dysregulated myeloid response emerging as a key driver of severe COVID-19 (15)(16)(17)(18)(19)(20)(21).…”

“…In the context of SARS-CoV-2, cross-sectional and prospective studies analysing peripheral blood, BALF and/or lung tissue samples from COVID-19 patients of differing disease severities have demonstrated significant virus-induced changes in the composition, phenotype and/or function of circulating and pulmonary neutrophil pools (Figure 1). Neutrophilia, robust NET generation and the presence of immature, immuno suppressive and pro-inflammatory neutrophil subsets are examples of some of the consequences of SARS-CoV-2 infection described thus far, with data suggesting that signatures of neutrophil activation are enriched in patients with severe COVID-19 and associated with poor clinical outcome (17)(18)(19)(20)(21). Combined with the results of rodent and non-human primate based studies, these data demonstrate striking similarities between SARS-CoV-2-induced changes in neutrophil biology and the neutrophil response triggered by other members of the Coronaviridae family such as Middle East respiratory syndrome coronavirus (MERS-CoV) and SARS-CoV (Table 1).…”

The Advent of COVID-19; Periodontal Research Has Identified Therapeutic Targets for Severe Respiratory Disease; an Example of Parallel Biomedical Research Agendas

“…A strong hyperactivation phenotype in peripheral PMNs has already been directly associated with severe cases of COVID-19, including increased phagocytosis, degranulation and chemotaxis, and increased expression of genes involved in pro-inflammatory cytokine release. Within these severe cases, the emergence of an immature PMN population, characteristic of emergency myelopoiesis, was the main difference observed between the immune responses in fatal and non-fatal cases of COVID-19 (73). NET formation in tissue injury and thrombotic complications are additional pathogenic mechanisms whereby circulating PMNs can lead to more severe COVID-19 (6,28,31,32,34).…”