Induction of dysfunctional CD14lowCD16- monocytes in acute COVID-19 infection

Introduction Severe COVID-19 disease is characterised by a state of hyperinflammation. As key producers of inflammatory mediators in blood, altered inflammatory activity of monocytes within some individuals may contribute to adverse disease outcomes. Methods Analysis of monocyte activity under settings of infection and inflammation can be challenged by activation-induced shedding of monocyte receptors traditionally used to identify monocyte subsets. Here, we utilised alternative, more robust immunophenotyping approaches to investigate the impact of COVID-19 infection on monocyte phenotype and inflammatory status. Results Immunophenotype analysis of cryopreserved peripheral blood mononuclear cells from unvaccinated, previously COVID-19 naive individuals (median age 43 years, range 21-95, n=42) with a PCR-confirmed acute COVID-19 infection indicated expansion of a novel population of CD14 low CD16- monocytes as compared to control individuals (adjusted p value <0.001) which was more pronounced in individuals with severe disease presentation (p=0.004 for mild vs severe disease). Expansion of this population during acute COVID-19 was confirmed using an alternative, CD14 and CD16-independent strategy for identifying monocyte subsets and was termed infection associated monocytes (IAM). IAM were refractory to ex vivo stimulation with lipopolysaccharide (LPS) and their proportion correlated with plasma levels of TNF and CXCL10 (p<0.05 for both). Monocyte subsets from individuals with acute COVID-19 exhibited reduced basal and LPS-stimulated production of inflammatory cytokines including IL-1β, TNF and IL-6, indicative of an inert monocyte state. Expansion of IAM and impaired inflammatory activity persisted for up to 3 months after acute COVID-19 infection. Discussion COVID-19 is associated with expansion of a novel subset of monocytes with impaired inflammatory activity that persist for at least 3 months after acute infection. Whether this population is uniquely expanded by COVID-19, and the long term implications of its persistence post-acute disease, remain to be defined.