Sunday, May 11, 2025
5/11/2025
Characterization of the SARS-CoV-2-mediated piracy of p38ß - COVID-19 has resulted in a significant burden on the human population following the emergence of SARS- CoV-2. Since the discovery of SARS-CoV-2 in 2019, millions have succumbed to infection due to an imbalanced host response orchestrated by the biology of the virus. Characterization of the interactions between SARS-CoV- 2 and the infected host have revealed that the virus manipulates a small subset of signaling pathways culminating in an overproduction of proinflammatory cytokines and chemokines juxtaposed to an underproduction of type I interferons, the central antiviral defense of vertebrates. An effort to identify kinase drug targets for the treatment of COVID-19, as kinases represent ideal druggable targets, found that the p38 family of mitogen-activated protein kinases (MAPKs) are among the most highly active kinases during SARS-CoV-2 infection. Moreover, perturbation of p38 kinases inhibited both virus replication and cytokine production. Thus, p38 kinases are promising drug targets to block both virus replication and the excessive inflammation that is a hallmark of severe COVID-19. In a subsequent study, a genetic perturbation approach was used to explore the p38/MAPK-SARS-CoV-2 interface and it was determined that the β isoform of the p38 kinase is an essential host factor for virus replication. Additionally, inhibition of p38β reduces the abundance of SARS-CoV-2 nucleocapsid protein (N), but not viral mRNA during infection. Contrary to the assumed pro-inflammatory activity of p38 kinases, findings suggested p38β negatively regulates the expression of inflammatory cytokines. Lastly, p38-dependent phosphosites on SARS-CoV-2 N were identified and mutation of these sites resulted in attenuated virus replication. Based on these data, the overarching goal of the research proposed here is to test the hypothesize that p38β phosphorylates both viral and host proteins to cumulatively promote SARS-CoV-2 replication and modulate the host response. To further characterize the SARS-CoV-2-p38β interface, Aim 1 will explore the mechanism(s) responsible for p38β's proviral activity and ascertain the contribution of this biology to the inflammatory response observed in the context of COVID-19. To this end, viral protein stability will be assessed with translation inhibitors and affinity-purification mass spectrometry to establish how p38β promotes the steady-state level of viral protein during infection. In parallel, different immune agonists and genetic perturbations will be tested in Aim 2 to assess the specificity of p38β-mediated downregulation of inflammatory cytokines and determine if altered expression of these cytokines contributes to the proviral activity of p38β. By characterizing these p38β-SARS-CoV-2 interactions, the research proposed here will enhance the understanding of SARS-CoV-2 biology, virus-host interactions, and p38β biology in order to inform the development of novel drug therapies critically needed for the treatment of COVID-19.
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