Severe form of COronaVirus Induced Disease (COVID)-19 in susceptible individuals is characterized by severe pneumonia, respiratory and multiorgan failure. The hallmark of severe COVID-19 is dysregulated immune response, cytokine storm and immune paralysis. However, key immunological mechanisms and indicators of this dysregulation are still unknown, which is hampering the development of efficient therapeutic protocols. Identifying predictive markers of mild and severe COVID-19, and the potential underlining immunological mechanisms driving COVID-19 immunopathogenesis, would open new possibilities for development of innovative therapeutic strategies for COVID-19.
Here we analyzed ~160 parameters of immune cells and humoral markers (including extracellular vesicles, EVs) in peripheral blood of 46 COVID-19 patients (26 with severe COVID-19 symptoms and 20 with mild symptoms) and 16 sex/age- matched healthy donors by standard and imaging flow cytometry, quantitative PCR, western blot and ELISA, followed by integrated correlation analyses with ~30 common clinical and laboratory parameters. We identified that, unlike severe COVID-19, mild COVID-19 patients display an increased levels of CD24+ and HLA-ABC+ EVs, and an increased proportion of activated ICOS+CD4+ T cells. The dysregulated T cell functions in severe COVID-19 were associated with lower expression of HLA-DR in different antigen-presenting cells subsets, down-regulated autophagy, and interferon responsive factor 8 (IRF-8), as well as with increased complement activation. These mechanisms lead to the expansion of myeloid derived suppressor cells (MDSC) and regulatory T cell subsets, which were identified as key drivers of immune paralysis in severe COVID-19. Therefore, the therapies targeting the impaired antigen-presentation, expansion, and functions of MDSCs, might provide great clinical benefit for severe COVID-19 by restoring T cell functions and anti-viral response.
The study was supported by the Ministry of Education, Science and Technological Development, Republic of Serbia (Contract No. 451-03-68/2020-14/200019, Contract No. 451-03-68/2020-14/200042, and Grant No. 451-03-921/2020-14/6 “Immunological aspects of SARS-CoV-2 infections”) and Serbian Academy of Sciences and Arts (Grant No. F31).
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