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Principal Investigator: Chang Liu
Organization: JOHNS HOPKINS UNIVERSITY
Fiscal Year: 2024
Award: $489,658
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY/ABSTRACT
Over the last two decades, three highly pathogenic human coronaviruses, including SARS-CoV-2, have
emerged, arguing that future deadly pandemics of new or re-emerging coronaviruses and other RNA viruses are
almost inevitable. The urgent need to treat these fatal infectious diseases has prioritized the discovery and
development of novel effective antivirals. However, despite the unprecedented efforts to address the COVID-19
crisis, highly effective COVID-19 therapeutics are severely limited due to the lack of a mechanistic understanding
of coronavirus replication and pathogenesis. Most of the current research and therapeutic development efforts
focus on SARS-CoV-2 RNA polymerase (RdRp) or spike protein, but their success can be severely undermined
by a unique SARS-CoV-2 proofreading mechanism that excises incorporated RdRp inhibitors or by the rapid
emergence of drug-resistant spike protein mutants. Therefore, it is imperative to develop innovative antiviral
strategies targeting distinct, and in some cases yet to be identified, essential components of the viral life cycle.
The intricate virus-host interplay constitutes a sophisticated regulatory network that dictates the outcome of virus
infection, affording promising opportunities to be explored for innovative antiviral therapeutics. However, current
knowledge of coronavirus-host interactions is mostly limited to the virus-host arms race in activating or blocking
the interferon-dependent signaling pathways or in competing for host translation machinery. By contrast, virus-
host interplay in coronavirus gene expression and regulation is largely uncharted territory. This major gap greatly
hinders the design of novel antiviral agents targeting these much-overlooked coronavirus-host interactions that
are critical for viral survival and host antiviral responses. The central objectives of this proposal are to define
novel molecular mechanisms and functional roles of multiple recently discovered SARS-CoV-2-host interactions
in modulating the viral replication and transcription processes and to identify new SARS-CoV-2-host interactions
linked to novel mechanisms of viral gene regulation. With a combination of structural biology, protein-RNA
biochemistry, single-molecule biophysics, cell virology, and computational approaches, we will accomplish these
tasks through three tightly interwoven aims. In Aim 1, we will determine the molecular and structural basis of
these newfound interactions between host factors and the viral replication-transcription machinery. In Aim 2, we
will delineate the biological functions of these crucial host factors in modulating viral replication and transcription.
In Aim 3, we will develop an innovative capture-identification-visualization experimental pipeline to discover new
host factors and novel viral replication-transcription-regulating mechanisms. Together, these studies will
establish an innovative conceptual framework to study coronavirus-host interactions and reveal new targets
for the development of novel anti-coronavirus therapeutics.
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