Project Details
Projekt
The role of MAPK pathways in SARS CoV-2 infection and COVID-19 disease (B13#)
Subject Area
Virology
Term
since 2020
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 194468054
The rapid world-wide spread of the novel COVID-19 infectious disease with high lethality numbers, manifests the urgent need for new therapeutic approaches to block viral replication, and to attenuate the lung damage caused by cytokine burst particularly in critically ill patients. The COVID-19 disease progresses in at least two stages, the first being dominated by damage caused by the virus itself, while the second stage occurs through a hyperinduction of cytokines. A very similar virus-induced immunopathological hypercytokinemia can be observed during lethal infections of humans with highly pathogenic avian influenza viruses (HPAIV). In the previous funding periods of the SFB we have unravelled a strong dependence of influenza virus (IAV) replication and HPAIV-induced disease on the Raf/MEK/ERK and the p38 mitogen activated protein kinase (MAPK) pathways. While we have recently elucidated the complete chain of events how the Raf/MEK/ERK pathway controls IAV replication, there is increasing evidence that the pathway also acts immunomodulatory. This implies that inhibitors of the cascade, that block the pathway on the level of the “bottleneck” kinase MEK, could act as novel antivirals with a dual benefit: directly, via impairing virus replication and indirectly, by re-balancing innate immune responses. Moreover, such a dual mode of action would also be perfectly suited to target both phases of the COVID-19 disease. We were just recently able to demonstrate this important impact of MEK inhibition, by demonstrating that the MEK inhibitor ATR-002 results in a sustained inhibition of SARS-CoV-2 propagation over time. Furthermore, we could also show that p38 inhibition leads to reduced expression of SARS-CoV-2 induced innate immune response genes and may also interfere with virus replication. On the basis of these data we hypothesize that the Raf/MEK/ERK pathway and/or the p38 pathway play a dual role in the COVID-19 disease by controlling viral replication on the one side and virus-induced cytokine expression on the other side. Thus inhibitors of these signalling cascades may be perfect candidates for novel anti COVID-19 drugs. To proof this hypothesis we will transfer our long-standing research expertise in antiviral and immune modulatory strategies obtained for the IAV model to SARS-CoV-2 infections and the COVID-19 disease. Beside molecular studies in cells and a human lung tissue explant model we will use the hACE2tg COVID-19 preclinical mouse model of our cooperation partners, to analyse in detail the contribution of the Raf/MEK/ERK and p38 MAPK pathways on the different stages of the COVID-19 disease progression. We will utilize established protocols from our labs to rapidly analyse the suitability of MEK and p38 inhibitors, that are already in clinical development, as potential new therapeutic interventions for COVID-19 patients.
DFG Programme
Collaborative Research Centres
Applicant Institution
Universität Münster
Project Head
Professor Dr. Stephan Ludwig
