# Dysregulation of the inflammatory response by Francisella tularensis

> **NIH VA I01** · HARRY S. TRUMAN MEMORIAL VA HOSPITAL · 2021 · —

## Abstract

Tularemia is a potentially fatal disease and the causative agent, Francisella tularensis (Ft), is one of few
bacterial pathogens that can infect both neutrophils (polymorphonuclear leukocytes, PMNs) and macrophages.
Notably, macrophages and neutrophils appear to play distinctly different roles in tularemia pathogenesis, with
macrophages acting as major vehicles for bacterial growth and dissemination, and PMNs playing a central role
in host tissue destruction. Neutrophils are short lived, and unlike other leukocytes are preprogrammed to
undergo apoptosis 24 h after release into the circulation. Tight spatial and temporal control of this process is
critical for elimination of infection and resolution of inflammation, and for this reason defects in PMN turnover
exemplify a dysregulated and ineffective inflammatory response that promotes tissue destruction and disease.
In keeping with this, we discovered that Ft inhibits human neutrophil apoptosis and markedly prolongs cell
lifespan, and demonstrated that this is achieved via effects on the intrinsic and extrinsic apoptosis pathways,
as well as changes in the neutrophil transcriptome that include significant differential expression of 365 unique
genes linked to apoptosis and cell fate. Nevertheless, how cell lifespan is prolonged is only partially
understood. Herein, we propose groundbreaking studies based on our discovery of neutrophil metabolic
reprogramming as a new mechanism for apoptosis inhibition. Our proposed studies are supported by extensive
preliminary data, and are highly innovative, as integrated manipulation of glycolysis and organelle function has
not been previously documented as a mechanism for regulation of PMN lifespan during infection. Potential
effects of these changes on bacterial growth and the influence of PMN metabolites on macrophage polarization
will also be determined. In addition, we recently identified bacterial lipoproteins (BLPs) as active factors in Ft
conditioned medium (CM) that extend PMN lifespan via a mechanism that is dependent on a common single
nucleotide polymorphism (SNP) in human TLR1 (rs5743618, T1805G) that significantly influences the severity
and lethality of sepsis as well as the outcomes of many infectious and inflammatory diseases, including but not
limited to tuberculosis, pyelonephritis, atherosclerosis, arthritis, lupus, colitis, and cancer. Elucidating the
mechanism(s) of BLP and TLR2/1-driven apoptosis inhibition is a second objective of this study. Our
experimental design will also utilize drugs that specifically target HIF-1 and TLR2, mitophagy, glycolysis or
other relevant signaling intermediates to identify points for therapeutic intervention that are expected to be
relevant to many diseases that affect Veterans. Our specific aims are: 1) To elucidate the mechanisms and
functional consequences of neutrophil metabolic reprogramming. 2) To elucidate the mechanisms of BLP and
TLR2/1-mediated apoptosis inhibition and potential for theraputic in...

## Key facts

- **NIH application ID:** 9898231
- **Project number:** 5I01BX002108-08
- **Recipient organization:** HARRY S. TRUMAN MEMORIAL VA HOSPITAL
- **Principal Investigator:** Lee-Ann H Allen
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2013-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898231

## Citation

> US National Institutes of Health, RePORTER application 9898231, Dysregulation of the inflammatory response by Francisella tularensis (5I01BX002108-08). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9898231. Licensed CC0.

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