# Enhancing neutrophil function in neutropenia-related pneumonia

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2020 · $442,500

## Abstract

Project Summary
Neutropenia and related infection are the most important dose limiting toxicities in hematopoietic cell
transplantation (HCT) and anti-cancer chemo- and radiotherapy, impacting on quality of life and clinical
outcomes, with the potential to cause death. Neutropenia-related pneumonias are involved in 40% infections at
a site other than blood alone and usually treated with broad-spectrum antibiotic therapy and G-CSF therapy.
However, not all patients respond to these treatments. The long-term goal of this project is to explore an
alternative strategy for treating/preventing neutropenia-related pneumonia, namely by enhancing neutrophil
function in neutropenic patients. We tried to achieve this by elevating intracellular PtdIns(3,4,5)P3 signaling
pathway which has been implicated in various neutrophil functions. We confirmed this concept by showing
that augmenting PtdIns(3,4,5)P3 signal by disrupting PTEN enhanced neutrophil function and bacterial
clearance, and reduced mortality rate in a murine model of neutropenia-related pneumonia. However, PTEN
disruption is associated with tumorigenesis, which rendered it unsuitable as a therapeutic target. Recently we
reported that PtdIns(3,4,5)P3 signal in neutrophils can also be elevated by disrupting IP6K1, an enzyme
responsible for the synthesis of IP7, a cytosolic molecule that negatively regulates PtdIns(3,4,5)P3 signaling.
Importantly, homozygous IP6K1 KO mice were viable and did not display any gross physical or behavioral
abnormalities. No tumors of any kind were discovered in these mice. Based on these intriguing results, we
hypothesize that disruption of IP6K1 should be a legitimate therapeutic strategy for the treatment of
neutropenia-related pneumonia. In the last funding period, we investigated the role of IP6K1 is regulating
neutrophil function in bacterial pneumonia. Consistent with the elevated PtdIns(3,4,5)P3 signaling in IP6K1
deficient neutrophils, disrupting the Ip6k1 gene (whole-body KO) or pharmacologically inhibiting IP6K1 activity
using a specific inhibitor TNP efficiently and effectively enhanced host bacterial killing capability, minimizing the
lung damage caused by both Gram-positive and Gram-negative bacterial pneumonia. Unexpectedly, inhibition
of IP6K1 reduced pulmonary neutrophil accumulation. We revealed that IP6K1-mediated inorganic
polyphosphate (polyP) production by platelets was essential for infection-induced neutrophil-platelet aggregate
(NPA) formation which facilitates neutrophil accumulation in alveolar spaces during bacterial pneumonia. As
part of our overall goal to further understand the role of IP6K1 and to design the best strategy to target IP6K1
in neutropenia-related pneumonia, we will continue to examine whether neutrophil-specific IP6K1 disruption is
sufficient to induce the elevated host defense (Aim 1). In addition, we will elucidate the role of platelet IP6K1 in
regulating pulmonary neutrophil accumulation in neutropenia-related pneumonia (A...

## Key facts

- **NIH application ID:** 9914117
- **Project number:** 5R01HL092020-10
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Hongbo R Luo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $442,500
- **Award type:** 5
- **Project period:** 2009-08-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9914117

## Citation

> US National Institutes of Health, RePORTER application 9914117, Enhancing neutrophil function in neutropenia-related pneumonia (5R01HL092020-10). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9914117. Licensed CC0.

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