We have previously shown that Low T3 syndrome is associated with serum markers, radiologic and clinical scores of COVID-19 severity and it can be considered as a novel biomarker of the severity of the disease (Endocrine Abstracts 2020, 70 AEP1091). With the aim to analyze the mechanisms that are at the basis of this condition as well as the pathways involved, we applied an integrative approach of multi-omics data. We performed: i) multiplex cytokine assay, using the Bio-Plex Pro Human Cytokine 27-Plex Immunoassay and a panel of cytokines and growth factors, ii) immune phenotyping by CyTOF analysis, using the Maxpar Direct Immune Profiling Assay, analyzed with the Maxpar Pathsetter automated package and visualized with the high-dimensional Cauchy Enhanced Nearest-neighbor Stochastic Embedding (Cen-se′) map and iii) transcriptome analysis by NanoString, using the nCounter PanCancer human IO 360 panel. We analyzed data from 4 patients affected by COVID-19, 2 with low FT3 serum values (≤ 1.7 pg/ml) and 2 with normal FT3 serum values (> 1.7 pg/ml and < 3.71 pg/ml). Results were compared to those obtained in 2 healthy control subjects. The study was approved by our Institutional Ethical Committee (RIF. CE 5773_2020). Cytokine assay indicated that some cytokines, namely IL-1b, IL-1ra, IL-6, IL-8, IL-10, IP-10, MCP-1 and MIP-1a, were increased in COVID-19 patients with low FT3 syndrome, some, namely IL-4, IL-7, IL-12, IL-13, Eotaxin, PDGF-bb and RANTES, were reduced and some others, namely IL-2, IL-9, IL-17A, FGF-basic, MIP-1b and TNF-a, were unchanged. CyTOF analysis indicated that Low T3 Syndrome in COVID-19 patients was associated with a reduction in CD45+, CD3+ T lymphocytes and CD19+ B lymphocytes, while there was an increase in CD3-/CD56+ NK cells as well as in CD14+ Monocytes. Finally, NanoString analysis showed a different expression pattern, with divergent allocation on the Principal Component Analysis plot and identified four genes, namely NLRP3, IFIT3, CD38 and CD79B, that were clearly deregulated in COVID-19 patients with Low T3 syndrome. NLRP3 was clearly downregulated while the IFT3, CD38 and CD79B were upregulated. In conclusion, we were able to identify, in our COVID-19 patients, specific immune and gene expression signatures associated with the occurrence of the Low T3 syndrome. Our approach allowed us to obtain insights on the mechanisms and on the pathways involved in the thyroid hormone regulation of immune response to SARS-CoV-2 infection and to identify new molecules of potential clinical utility in the management of severe COVID-19.
22 May 2021 - 26 May 2021