[R21] Mechanistic understanding of influenza virus inhibition by non-canonical ISG15
Ente: National Institute of Allergy and Infectious Diseases
Scadenza: 2028-07-31
Importo max: 231.000 EUR
Paese: US
Descrizione
PROJECT SUMMARY
Viruses are highly evolved to infect specific cell types in permissive host species. This tropism is defined by the
gene expression repertoire of their “preferred” host cell type, which provides the necessary co-factors to facilitate
virus replication. Host gene expression is finely tuned to respond to infection, and vertebrate hosts rapidly induce
a suite of genes, called interferon stimulated genes (ISGs), upon pathogen sensing that create an inhospitable
environment for viral replication. Influenza virus infections cause devastating health consequences across the
globe yearly. These viruses have a broad species repertoire and can replicate and cause disease in many
different vertebrates. The human gene ISG15 is rapidly and abundantly produced upon pathogen sensing, which
led to the early hypothesis with strong supporting data in mice and human cells that it is generally antiviral against
influenza virus. Since its discovery, the last ~50 years of research have shown that ISG15 is involved in host-
pathogen interactions, immune homeostasis, and tumorigenesis. These broad arrays of functions occur through
at least three major mechanisms: in the posttranslational modification coined ISGylation, as an unconjugated
intracellular interferon suppressor, and as an extracellular proinflammatory cytokine. Regulation of gene
expression is more complex than activation or repression. Rather, genes are also expressed as a spectrum of
isoforms governed by alternative RNA splicing where different isoforms of the same gene can have variable
coding sequences. Our prior work evaluated two influenza virus host factors that, through alternative splicing,
mediate their positive or negative impact on virus survival. This work and others' provided us the motivation to
re-examine ISG alternative splicing. Through long-read RNA-sequencing, we identified a novel transcript isoform
of ISG15 that we call here non-canonical ISG15 (ncISG15). We observe that ncISG15 is produced upon
interferon stimulation or influenza virus infection, and that the expressing this transcript potently restricts
influenza virus genomic replication and progeny production. Additional observations suggest that ncISG15 can
modify a similar yet distinct suite of host proteins compared to ISG15, but this modification is not required for
ncISG15 antiviral function. Strikingly, the viral interferon antagonist protein NS1 counteracts the antiviral activity
of ncISG15, and endogenous ncISG15 functionally restricts influenza virus infection. Preliminary data suggest
that ncISG15 expression corresponds with a decrease in the viral NP protein, and NS1 expression corresponds
with a decrease in ncISG15 expression. To fully understand the impact and elucidate the mechanism by which
ncISG15 inhibits influenza virus, we propose two independent lines of research: 1) determine whether protein
and/or RNA turnover mediate the observed decrease abundance in NP by ncISG15 or ncISG15 by NS1, and 3)
defi
Istituzione: LOYOLA UNIVERSITY CHICAGO
PI: Steven Frederick Baker
Progetto: 1R21AI202159-01
Settori: National Institute of Allergy and Infectious Diseases
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