COVID-19 and immunological regulations - from basic and translational aspects to clinical implications

Abstract

The COVID-19 pandemic caused by SARS-CoV-2 has far-reaching direct and indirect medical consequences. These include both the course and treatment of diseases. It is becoming increasingly clear that infections with SARS-CoV-2 can cause considerable immunological alterations, which particularly also affect pathogenetically and/or therapeutically relevant factors. Against this background we summarize here the current state of knowledge on the interaction of SARS-CoV-2/COVID-19 with mediators of the acute phase of inflammation (TNF, IL-1, IL-6), type 1 and type 17 immune responses (IL-12, IL-23, IL-17, IL-36), type 2 immune reactions (IL-4, IL-13, IL-5, IL-31, IgE), B-cell immunity, checkpoint regulators (PD-1, PD-L1, CTLA4), and orally druggable signaling pathways (JAK, PDE4, calcineurin). In addition, we discuss in this context non-specific immune modulation by glucocorticosteroids, methotrexate, antimalarial drugs, azathioprine, dapsone, mycophenolate mofetil and fumaric acid esters, as well as neutrophil granulocyte-mediated innate immune mechanisms. From these recent findings we derive possible implications for the therapeutic modulation of said immunological mechanisms in connection with SARS-CoV-2/COVID-19. Although, of course, the greatest care should be taken with patients with immunologically mediated diseases or immunomodulating therapies, it appears that many treatments can also be carried out during the COVID-19 pandemic; some even appear to alleviate COVID-19.

Figure 1

Schematic representation of immune activation in COVID‐19. SARS‐CoV‐2 preferentially attacks pneumocytes, pericytes and muscle cells. Numerous mediators, for example IL‐1, IL‐6 and TNF, are induced mainly via the interferon and NF‐κB signaling pathways. A balanced immune response leads to elimination of the viruses and healing (left side). In predisposed patients, however, a so‐called cytokine storm with an uncontrolled increase in proinflammatory mediators can also occur. This may lead to severe organ damage (right side).

Figure 2

Potential influence of immunomodulatory therapies on COVID‐19. In COVID‐19 patients treated with immunomodulatory drugs, different effects can occur, which must be weighed against each other, as there is a fine‐tuned balance of possible beneficial and detrimental effects. Some of these are schematically depicted here. For example, immunomodulators could influence cytokine formation and action, virus entry into cells, thromboembolic events or lymphocyte functions. On the other hand, the course of immune‐mediated diseases could also be altered by infection with SARS‐CoV‐2. Many aspects of how drug therapies influence the immunological balance are not yet known. Nevertheless, it is becoming apparent that some specific therapies, such as blocking IL‐6, can positively influence the excessive immune response triggered by COVID‐19. On the other hand, checkpoint inhibitors could act synergistically with the immune activation in COVID‐19. Further details are explained in the text.