# Determinants of human neutrophil fate after phagocytosis

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2020 · $486,758

## Abstract

Human innate immune response to microbes depends on the coordinated interactions among a variety of
cells and secreted factors, with polymorphonuclear leukocytes (PMN) typically prominent among the first
responders. In their capacity as phagocytic cells, PMN sequester ingested prey in membrane-bound
phagosomes, where oxidants from the NADPH oxidase and proteins from granules synergize to create a toxic
environment that promotes death and degradation of the engulfed microbe. In certain settings, a significant
fraction of ingested microbes survives within PMN. The persistence of viable microbes within phagosomes not
only provides a mechanism for sustained infection but also can modulate the local inflammatory tone by
altering the programmed cell death of PMN and promoting PMN release of proinflammatory cytokines.
Interference with phagocytosis-induced apoptosis of PMN (PICD), either by delaying apoptosis, as seen with
N. gonorrhoeae (Ngc) or engaging a novel necrotic cell death pathway, as seen with Staphylococcus aureus
(SA), thwarts resolution of the inflammatory response and causes release of host-derived danger signals that
promote inflammation and secondary tissue damage. Thus, effective innate immune response requires not
only death and degradation of invading microbes but also resolution of inflammation and reestablishment of
homeostasis. The overarching hypothesis of this proposal is that the failure of PMN to undergo apoptotic
cell death derails the resolution phase of the inflammatory response and instead amplifies disease.
 Because activated human PMN (hPMN) and their secreted products can sculpt the inflammatory tone in
tissue, we propose to use Ngc and SA -- both human pathogens that survive within PMN, alter phagocytosis-
induced cell fate pathways and elicit profound inflammatory local changes – as tools to probe mechanisms that
dictate phagocyte fate and timely resolution of inflammation. We will pursue two Specific Aims:
Aim 1: To determine the mechanisms that regulate human PMN fate
.
 A. Determine the signaling pathways that differentially direct hPMN towards survival vs programmed
cell death (apoptosis vs primary necrosis).
 B. Determine the composition and activities of the ripoptosome (intracellular complexes) in hPMN after
phagocytosis
 C. Determine the role of Proliferating Cell Nuclear Antigen (PCNA) in the fate of phagocytosing hPMN
Aim 2: To determine the mechanisms underlying hPMN secretion of IL-1β during phagocytosis
A. Identify the role of inflammasomes in IL-1β production by hPMN during phagocytosis
B. Determine the importance of serine proteases in generation of IL-1β
C. Determine the role of Receptor-interacting kinase-3 (RIPK-3) in hPMN IL-1β secretion

## Key facts

- **NIH application ID:** 9851806
- **Project number:** 5R01AI132335-03
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** William M. Nauseef
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $486,758
- **Award type:** 5
- **Project period:** 2018-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9851806

## Citation

> US National Institutes of Health, RePORTER application 9851806, Determinants of human neutrophil fate after phagocytosis (5R01AI132335-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9851806. Licensed CC0.

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