# Leveraging Pathogen-Host Networks to Identify Virus-specific and Estradiol-regulated Mechanisms during Respiratory Infection

> **NIH NIH R21** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $194,425

## Abstract

ABSTRACT
Respiratory viruses, such as influenza and SARS-CoV-2, interact with distinct molecular pathways in human
cells to promote virus replication and alter immune activity. When considering patient cohort variability, morbidity
and mortality are often higher for women than men for select influenza virus infections, exemplified in the 2009
H1N1 pandemic. Estradiol, a major sex hormone, has been shown to impact virus replication in a sex-specific
manner. Yet much remains unknown as to the pathways different viruses engage to promote infection and alter
immune activity or what pathways link estradiol activity to virus replication. This research program uses recently
developed bioinformatics algorithms and NIAID-supported, published datasets in order to reveal new pathways
and molecules involved in infection with influenza viruses and SAR-CoV-2 (Aim 1) and in infection in respiratory
cells derived from women and treated with estradiol (Aim 2). More specifically, we will use two dynamic network
perturbation algorithms, ProTINA and DeltaNeTS+, to create dynamic mathematical models of intracellular
signaling in order to predict important disease modulators. Dynamic network perturbation analysis will be applied
to virus-specific, virus-host interaction networks and host gene expression data induced by each virus. For Aim
2, we have identified gene expression data from influenza-infected nasal cells from female donors that are
pretreated with estradiol. We will validate ProTINA’s and DeltaNeTS+ ability to identify host factors of virus
replication using results from published siRNA- and CRISPR-based screens. After the validation, we will perform
an in-depth characterization of the most significant proteins identified in order to generate new hypothesis on the
host pathways that are involved in infection with different respiratory viruses or that interact with estradiol during
infection.

## Key facts

- **NIH application ID:** 10863893
- **Project number:** 5R21AI174080-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Jason Edward Shoemaker
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $194,425
- **Award type:** 5
- **Project period:** 2023-06-09 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10863893

## Citation

> US National Institutes of Health, RePORTER application 10863893, Leveraging Pathogen-Host Networks to Identify Virus-specific and Estradiol-regulated Mechanisms during Respiratory Infection (5R21AI174080-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10863893. Licensed CC0.

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