DIFFERENTIALLY EXPRESSED IMMUNOLOGICAL GENES in MILD and SEVERE CASES of COVID-19

ABSTRACT

Background: Coronavirus disease 2019 (COVID19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has varied clinical presentations from mild subclinical to severe disease with high mortality. Our aim was to determine whether examining immune-related gene expression early in infection could predict progression to severe disease. Methods: In subjects of the All Ireland Infectious Diseases Cohort study, we analysed expression of 579 genes with the NanoString nCounter Immunology panel in peripheral blood mononuclear cells in those with confirmed SARS-CoV-2 infection collected within 5 days of symptom onset and matched SARS-CoV-2 negative controls with respiratory infection. Subsequent maximum COVID19 disease severity was classified as mild or severe. Read counts were normalized using panel housekeeping genes. Expression changes in severity groups were estimated against control baseline. Results: Between April and July of 2020, we recruited 120 subjects, 62 with COVID19 and 58 controls, with average age 59 y.o. (IQR 34-88), 66% males and 69% Caucasian ethnicity. Maximal disease severity was used to separate COVID19 cases into mild (n=31) and severe (n=31). We identified 20 significantly deregulated genes between those with COVID19 and controls (;log2 fold;>0.5, p<0.05, Benjamin-Yekutieli p-adjustment). Function of 12 of these genes related to cytokine signaling, 9 upregulated genes to type I interferon signaling (MX1, IRF7, IFITM1, IFI35, STAT2, IRF4, PML, BST2, STAT1), while 7 downregulated genes mapped to innate immune function (IRF7, ICAM2, SERPING1, IFI16, BST2, FCER1A, PTK2). Expression in the severe group showed downregulation of FCER1A (innate immunity regulation), IL1B and TNF (inflammatory cytokines), and PTGS2 (inflammatory mediator) and greater upregulation of TNFSF4 (cytokine signaling) and PTK2 (innate immunity). Mild cases presented higher upregulation of IFIT2 (type I interferon signaling). Conclusion: Observed early downregulation of regulators and mediators of inflammation in those who developed severe COVID19, suggested dysregulation of inflammation. Specifically, IFIT2 upregulation in mild cases and FCER1A downregulation in severe cases, points to early differences in host responses centered on deregulation of the interferon and inflammation responses. Whether these patterns reflect delayed interferon involvement in pathways to control the infection and contribute to pathological inflammation and cytokine storms observed in severe COVID19 requires further research.