# RNA targeting specificity and immunomodulation by the influenza A virus ribonuclease PA-X

> **NIH NIH F31** · TUFTS UNIVERSITY BOSTON · 2021 · $41,782

## Abstract

PROJECT SUMMARY/ABSTRACT
Although inflammation is needed for the host to defend itself against influenza infection, too much inflammation
is detrimental to the host, and contributes to morbidity and mortality. Yet, available therapeutics are solely
antiviral and do not prevent inflammation-driven lung damage, mostly because how inflammation is regulated
during influenza infection is not fully understood. As a result, influenza virus still kills tens of thousands of
people every year in the US alone, and up to half a million worldwide. Since influenza itself has evolved
mechanisms to regulate the host innate immune and inflammatory response, studying these mechanisms is
one strategy to start designing new avenues of therapeutic intervention. Influenza A virus modulates host
responses to infection in part through its virus-encoded ribonuclease (RNase) PA-X. Indeed, mutated PA-X-
deficient viruses cause higher levels of inflammatory responses and increased mortality compared to wild-type
viruses in animal models of infection. While PA-X globally degrades host mRNAs, how this activity specifically
leads to modulation of the immune and inflammatory response is not known. Through transcriptomic analysis
of infected and PA-X expressing cells, the Gaglia lab has found that PA-X actually targets specific subsets of
RNAs, while sparing others. Importantly, innate immune genes are preferentially targeted by PA-X, consistent
with its in vivo anti-inflammatory phenotype. Our RNAseq data also uncovered that spliced RNAs are more
susceptible to PA-X degradation than intronless RNAs, a specificity that I confirmed using reporter constructs,
suggesting a mechanistic link between PA-X and splicing. However, how this splicing based mechanism allows
PA-X to modulate innate immunity and inflammation is unknown. In the proposed work, I will test the
hypothesis that PA-X exploits RNA splicing to target nascent RNAs, allowing PA-X to down-regulate genes that
are induced transcriptionally during infection and modulate the host innate immune response and inflammation.
In Aim 1, I will study the role of specific splicing steps in recruiting PA-X to RNAs. In Aim 2, I will explore the
link between PA-X targeting and transcription, and study the preferential targeting of nascent RNAs. In Aim 3, I
will connect these findings to regulation of innate immunity and inflammation by PA-X in a biologically relevant
3D lung culture model. The Gaglia lab provides the best training environment for me to complete this work, as
shown by my recent first-author publication, which expanded our understanding of the molecular mechanism of
action of PA-X. I will acquire the technical and conceptual skills that are required for this project through my
mentor’s comprehensive knowledge of viral control of host gene expression and high-throughput sequencing
dataset analysis, my co-mentor’s extensive experience in RNA work and transcription, and our collaborators’
expertise in human primary bronchia...

## Key facts

- **NIH application ID:** 10231509
- **Project number:** 1F31AI154587-01A1
- **Recipient organization:** TUFTS UNIVERSITY BOSTON
- **Principal Investigator:** Lea Gaucherand
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $41,782
- **Award type:** 1
- **Project period:** 2021-09-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10231509

## Citation

> US National Institutes of Health, RePORTER application 10231509, RNA targeting specificity and immunomodulation by the influenza A virus ribonuclease PA-X (1F31AI154587-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10231509. Licensed CC0.

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