# Global Gene Expression Responses of Francisella tularensis to intracellular Infection of Human Alveolar Macrophages

> **NIH NIH R21** · UNIVERSITY OF WASHINGTON · 2021 · $288,407

## Abstract

Francisella tularensis, the cause of tularemia, is a highly virulent intracellular pathogen and a Tier 1 select
agent with the potential to cause severe disease as an airborne bioweapon. The virulence of F. tularensis is
linked to its capacity to evade recognition by the host, suppress immune responses, and replicate inside of
host cells. Because specialized facilities are required for work with fully virulent F. tularensis, much of the
research in this field has been done with closely related but less virulent strains of Francisella, including
Francisella novicida, which is highly virulent for mice but not for humans. Pneumonia is the most lethal form of
tularemia, and the target cell of Francisella in the lungs is the alveolar macrophage. The interaction of F.
tularensis with human AM has not been studied. The overall goal of this project is to identify key mechanisms
underlying the parasitism of human AM, using an approach that compares the interactions of human AM with
fully virulent and attenuated strains of Francisella.
Specific Aim 1: Profile F. tularensis global gene expression responses within primary human alveolar
macrophages (AM) at distinct phases of bacterial intracellular location. Identify changes in Francisella gene
expression in i) bacterial cultures and ii) primary human AMs at time-points corresponding to distinct phases of
the bacterial intracellular cycle (phagosomal/cytosolic/replicative). AMs will be infected with either highly virulent
F. tularensis subsp. tularensis (Ft), a deletion mutant of Ft lacking type VI secretion, or attenuated F.tularensis
subsp novicida (Fn) to identify bacterial responses to the host environment that are unique to virulent infection.
Specific Aim 2: Identify F. tularensis gene responses that target host immune pathways through
correlation with defensive protein production. Innate immune responses in AMs infected with either Ft or Fn
will be assessed by measuring cytokine and chemokine. Multiple statistical data integration approaches will be
used to model the relationship between host inflammation with bacterial gene responses and bacterial growth
kinetics measured in Aim 1. This will identify bacterial responses unique to virulent Ft and that correlate with
suppression of AM innate immune responses at distinct stages of the bacteria's intracellular lifecycle.
Specific Aim 3: Model F. tularensis metabolic gene expression changes within primary human AM. Use
a metabolic network reconstruction of F. tularensis subsp. holarctica vaccine strain (LVS) to include genome
annotations from Ft and Fn and use this model to compute pathway usage across the metabolic network. Gene
expression data generated in Aim 1 will be mapped against this updated model to explore shifts in pathway
usage in highly virulent and attenuated Francisella strains at distinct stages of the intracellular lifecycle.
These studies will yield novel insights into the interaction of F. tularensis with human AM that will guide
subseq...

## Key facts

- **NIH application ID:** 10104807
- **Project number:** 1R21AI156263-01
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Shawn J. Skerrett
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $288,407
- **Award type:** 1
- **Project period:** 2021-03-25 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10104807

## Citation

> US National Institutes of Health, RePORTER application 10104807, Global Gene Expression Responses of Francisella tularensis to intracellular Infection of Human Alveolar Macrophages (1R21AI156263-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10104807. Licensed CC0.

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