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Principal Investigator: Raphaela Goldbach-Mansky
Organization: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Fiscal Year: 2021
Award: $35,545
Funding agency: National Institute of Allergy and Infectious Diseases
In collaboration with the NIAID COVID consortium we have analyzed longitudinally collected whole blood samples collected for RNA isolation from 84 adult patients hospitalized with severe COVID.
We also assessed serum samples from a larger panel of adult patients hospitalized with severe COVID (from Brescia n=567, Monza 77 and Pavia: 43) for serum IL-18, IL-18BP and CXCL-9 and a subset for spike-2 protein levels and other inflammatory markers released from innate and adaptive immune cells and/or surrounding tissues. Our data showed overall reduced Type I IFN signaling and variably immune activation of NFKB and Type II IFN (IFN gamma) regulated genes in hospitalized patients but not in patients with milder disease and healthy controls (Abers et al. JCI Insight 2021;6(1):e144455).
The transcriptional score derived from the analysis of 28 type I IFNregulated genes, was increased in a subset of patient over healthy controls but the type I IFN score of COVID-19 patients was significantly lower than that observed in monogenic type I IFNopathies. We also found that the normalized transcriptional levels of IFNA2 of circulating leukocytes did not correlate with the protein IFN-2a blood levels. Furthermore, normalized IFNA2 transcripts only weakly correlated with the 28-gene type I IFN score in COVID-19 patients which was in contrast to their significant correlation in patients with monogenic IFNopathies together with the decreased numbers of circulating plasmacytoid DCs (pDCs) and impaired production of type I IFN by circulating pDCs in COVID-19 patients reported by others (10, 16, 19) suggested non-hematopoietic sources of IFN alpha in COVID patients.
A multivariable analysis of patients first samples revealed 12 biomarker-associated with systemic and monocyte activation (sTNFRSF1A, IL-6, CCL2, ferritin, IL-15), damage (MMP-9, soluble ST2 sST2), neutrophil activation (NGAL, S100A9) endothelial activation (sVEGFR1) and T cell activation (IL-2) correlated with disease severity and mortality. Among these, sST2, sTNFRSF1A, IL-10, and IL-15 were consistently higher throughout the hospitalization in patients who died versus those who recovered. (Abers et al. JCI Insight 2020)
The inadequately low IFN alpha response contributes to the severe disease manifestations of COVID19. In another consortium study a subset of patients with particularly low and therefore impaired IFN who had life-threatening coronavirus disease 2019 had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon- (IFN-), 13 types of IFN- or against both in 10.2% of the cohort patients at the onset of critical disease. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in over 600 individuals with asymptomatic or mild SARS-CoV-2 infection. (Bastard et al. Science 2020, 370, eabd4585). This study identified the presence of anti-type I IFN antibodies as risk factors that suppress the IFN response and with among other host factors predisposes to severe COVD19.
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