Upregulation of CD55 complement regulator in distinct PBMC subpopulations of COVID-19 patients is associated with suppression of interferon responses.

Complement activation has been verified in COVID-19 patients by both increased serum levels of complement factors C3a and C5b-9 and increased complement deposition at the tissue levels. Complement regulatory proteins (CRPs) CD55, CD46, CD59 and CR1 act to control complement overactivation and eliminate complement deposition and cell lysis. The aim of the study was to investigate the expression of CRPs in COVID-19 in order to identify potential dysregulated expression patterns of CRPs and address whether these may contribute to disease pathogenesis. Single cell RNA-sequencing (scRNA-seq) analysis performed on isolated PBMCs revealed an increase of CD55 expression in severe and critical COVID-19 patients compared to healthy controls. This increase was also detected upon integrated subclustering analysis of the monocyte, T cell and B cell populations. Flow cytometric analysis verified the distinct pattern of upregulated CD55 expression in monocyte and T cell sub populations of severe COVID-19 patients. This upregulation was associated with decreased expression of interferon stimulated genes (ISGs) in patients with severe COVID-19 suggesting a potential suppressor effect of CD55 on interferon responses. The present study identifies a COVID-19 specific CD55 expression pattern in PBMC subpopulations that coincides with reduced interferon responses thus indicating that the complement regulator CD55 may contribute to COVID-19 pathogenesis.

Blood transcriptomes of anti-SARS-CoV2 antibody positive healthy individuals with prior asymptomatic versus clinical infection

Despite tremendous efforts by the international research community to understand the pathophysiology of SARS-CoV-2 infection, the reasons behind the clinical variability, ranging from asymptomatic infection to lethal disease, are still unclear. Existing inter-individual variations of the immune responses, due to environmental exposures and genetic factors, may be critical to the development or not of symptomatic disease after infection with SARS-CoV-2, and transcriptomic differences marking such responses may be observed even later, after convalescence. Herein, we performed genome-wide transcriptional whole-blood profiling to test the hypothesis that immune response-related gene signatures may differ between healthy individuals with prior entirely asymptomatic versus clinical SARS-CoV-2 infection, all of which developed an equally robust antibody response. Among 12.789 protein-coding genes analyzed, there were only six and nine genes with significantly decreased or increased expression, respectively, in those with prior asymptomatic infection (n=17, mean age 34 years) relatively to those with clinical infection (n=15, mean age 37 years). All six genes with decreased expression (IFIT3, IFI44L, RSAD2, FOLR3, PI3, ALOX15), are involved in innate immune response while the first two are interferon-induced proteins. Among genes with increased expression six are involved in immune response (GZMH, CLEC1B, CLEC12A), viral mRNA translation (GCAT), energy metabolism (CACNA2D2) and oxidative stress response (ENC1). Notably, 8/15 differentially expressed genes are regulated by interferons. Our results suggest that an intrinsically weaker expression of some innate immunity-related genes may be associated with an asymptomatic disease course in SARS-CoV-2 infection. Whether a certain gene signature predicts, or not, those who will develop a more efficient immune response upon exposure to SARS-CoV-2, with implications for prioritization for vaccination, warrant further study.