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Principal Investigator: Christina Higgins
Organization: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
Fiscal Year: 2024
Award: $48,974
Funding agency: National Institute of Allergy and Infectious Diseases
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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