Abstract
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. Epithelial-immune cell interactions and elevated cytokine and chemokine levels, i.e. cytokine storm, seem to play a central role in severity and lethality in COVID-19. The present perspective places a central cellular pro-inflammatory signal pathway, NF-κB, in the context of recently published data for COVID-19 and provides a hypothesis for a therapeutic approach aiming at the simultaneous inhibition of whole cascades of pro-inflammatory cytokines and chemokines. The simultaneous inhibition of multiple cytokines/chemokines is expected to have much higher therapeutic potential as compared to single target approaches to prevent cascade (i.e. redundant, triggering, amplifying, and synergistic) effects of multiple induced cytokines and chemokines in critical stage COVID-19 patients.
Highlights
Coronaviruses—enveloped positive-sense, single-stranded RNA viruses—are broadly distributed in humans and animals
We have previously shown that elevated cytokine release of IL-a/ b, IL-6, MIP-1b, RANTES, and TNF-a induced by highly pathogenic avian H5N1 influenza A virus was significantly reduced by application of the proteasome inhibitor VL-01 in vivo [39]
Various studies as referenced in the present review have shown that highly stimulated epithelial-immune cell interactions leading to highly dysregulated exuberant inflammatory responses with significantly elevated cytokine and chemokine release, play a central role in severity and lethality in various acute respiratory viral infections, including Influenza A H5N1, highly pathogenic H1N1, SARSCoV, MERS-CoV, and SARS-CoV-2
Summary
Coronaviruses—enveloped positive-sense, single-stranded RNA viruses—are broadly distributed in humans and animals. While most human coronavirus (hCoV) infections show mild symptoms, there are highly pathogenic hCoV, including the severe acute respiratory syndrome virus (SARSCoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV), with 10 and 37% mortality, respectively. The novel coronavirus SARS-CoV-2 with more than 42 mio infected persons and 1.2 mio deaths worldwide (https://coronavirus.jhu.edu/) End of October 2020 has become a global pandemic with enormous medical and socio-economic burden. Patients infected with SARSCoV-2 show a wide spectrum of clinical manifestations ranging from mild febrile illness and cough up to acute respiratory distress syndrome (ARDS), multiple organ failure, and death, i.e. a clinical picture in severe cases that is very similar to that seen in SARS-CoV and MERS-CoV infected patients. While younger individuals show predominantly mild-to-moderate clinical symptoms, elderly individuals frequently exhibit severe clinical manifestations [1,2,3,4].
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