# Quantifying the genetic and environmental factors driving avian influenza spillover

> **NIH NIH R00** · UNIVERSITY OF PENNSYLVANIA · 2022 · $249,000

## Abstract

PROJECT SUMMARY
Past influenza cross-species transmission events have lead to devastating human pandemics. H5N1 is an
avian influenza virus that has caused recurrent, high pathogenicity human infections since 1997. Humans
usually acquire H5N1 through interaction with live birds, and mounting evidence suggests that H5N1 circulation
in poultry is strongly linked to human infection. Despite this, the genetic and environmental factors that
promote H5N1 circulation in poultry remain unknown. A predominant hypothesis is that wild birds seed
new viruses into poultry, and humans acquire infection via poultry interaction. However, the rate of
transmission between wild birds and poultry has never been estimated. Although certain husbandry
practices like outdoor rearing and transport to large, live poultry markets are hypothesized to enhance H5N1
circulation, the relative contributions of these husbandry practices have never been systematically
assessed. Finally, virologic studies have produced a catalogue of mutations associated with human adaptation
in laboratory and animal studies, which are currently used to query emerging H5N1 strains and assess
pandemic risk. However, many human-infecting H5N1 strains lack known markers of adaptation, and it is
unclear whether these mutations predict spillover risk in nature. In this proposal, I will use phylogenetic
and statistical methods to determine the genetic and environmental drivers of H5N1 cross-species
transmission through 3 specific aims. Completion of these projects with my mentors and co-mentors will
allow me to achieve my career goal of transitioning to an independent faculty role by the end of the K99 phase.
1. I will use a recently developed structured coalescent model to estimate the rate of H5N1
transmission between wild birds, poultry, and humans. I hypothesize that cross-species transmission
occurs frequently between wild birds and poultry, but only a small subset of lineages circulate long-term. I
expect to observe ongoing transmission in poultry, but not in humans.
2. I will use phylogenetic and statistical methods to determine the environmental and husbandry
practices that promote long-term H5N1 circulation in poultry. I hypothesize that short-term spillover events
will be associated with outdoor poultry housing and rice cropping. Long-term establishments will be correlated
with poor vaccination coverage and introduction into a large poultry market.
3. Elucidate genetic and phenotypic determinants of cross-species transmission. I will combine the
power of a genome-wide scan with phenotypic validation to identify the genetic correlates of avian influenza
spillover. I hypothesize that H5N1 lineages that are prone to human spillover will be enriched for mutations
experimentally linked to host switching. I predict that our scan will identify mutations that elicit improved human
receptor binding, enhanced replication in mammalian cells, and abrogation of interferon production.

## Key facts

- **NIH application ID:** 10659289
- **Project number:** 4R00AI147029-04
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Louise Hillier Moncla
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $249,000
- **Award type:** 4N
- **Project period:** 2022-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10659289

## Citation

> US National Institutes of Health, RePORTER application 10659289, Quantifying the genetic and environmental factors driving avian influenza spillover (4R00AI147029-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10659289. Licensed CC0.

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