  Patients infected with SARS-CoV-2 show a wide spectrum of clinical
manifestations ranging from mild febrile illness and cough up to acute
respiratory distress syndrome, multiple organ failure and death. Data from
patients with severe clinical manifestations compared to patients with mild
symptoms indicate that highly dysregulated exuberant inflammatory responses
correlate with severity of disease and lethality. Significantly elevated
cytokine levels, i.e. cytokine storm, seem to play a central role in severity
and lethality in COVID-19. We have previously shown that excessive cytokine
release induced by highly pathogenic avian H5N1 influenza A virus was reduced
by application of proteasome inhibitors. In the present study we present
experimental data of a central cellular pro-inflammatory signal pathways,
NF-kappaB, in the context of published clinical data from COVID-19 patients and
develop a hypothesis for a therapeutic approach aiming at the simultaneous
inhibition of whole cascades of pro-inflammatory cytokines and chemokines via
blocking the nuclear translocation of NF-kappaB by proteasome inhibitors. The
simultaneous inhibition of multiple cytokines/chemokines using clinically
approved proteasome inhibitors is expected to have a higher therapeutic
potential compared to single target approaches to prevent cascade (i.e.
triggering, synergistic, and redundant) effects of multiple induced cytokines
and may provide an additional therapeutic option to be explored for treatment
of critical stage COVID-19 patients.
