# Selective modulation of neutrophils in critical illness

> **NIH NIH R35** · RHODE ISLAND HOSPITAL · 2020 · $402,500

## Abstract

Abstract
 Critical illness describes the life-threatening state caused by immune dysfunction that can occur
following traumatic injury, shock, burn or major surgery. Trauma-induced immune incompetence enhances
susceptibility to secondary infections that are a significant cause of mortality in hospital ICUs. Neutrophils, the
most abundant leukocyte in the circulation, are critical for host defense against bacterial and fungal pathogens,
but they also induce bystander tissue injury due to the non-specific and cytotoxic nature of their antimicrobial
arsenal. The effects of trauma on neutrophils contribute to immune dysfunction and include a significant deficit
in neutrophil capacity to find and fight infection, coupled with a primed phenotype associated with inducing
tissue damage. The long-term goals of my research program are to understand mechanisms of neutrophil
recruitment and effector function in health and disease. This MIRA application describes our synergistic
approaches to identifying and understanding mechanisms of neutrophil pathobiology during critical illness.
First, we have established an innovative approach to derive neutrophils ex vivo that circumvents the technical
barriers to their genetic modification. This enables us to perform multiplexed forward genetic screening using
CRISPR-Cas9 in neutrophils, and thereby identify new mechanistic aspects of their recruitment (e.g., integrin
activation) and antimicrobial function (e.g., phagocytosis). Second, we have established a mouse model of
critical illness by respiratory infection secondary to hemorrhagic shock. As the lungs are particularly
susceptible to infection secondary to trauma and are also prone to neutrophil-mediated injury, this model
provides a means to evaluate new targets/strategies for promoting selective aspects of neutrophil function to
enhance host defense without exacerbating tissue damage. Finally, we will apply human trauma patient
material (blood, plasma, lung fluid) to these approaches to probe disease-specific mechanisms of the
neutrophil response. Since our studies will interrogate fundamental biological mechanisms, such as integrin
activation, this work will also have broad impact on multiple fields. Together, these integrated approaches will
address major knowledge gaps in neutrophil biology by spanning the molecular, cellular and organism/disease
levels of experimentation.

## Key facts

- **NIH application ID:** 9985612
- **Project number:** 5R35GM124911-04
- **Recipient organization:** RHODE ISLAND HOSPITAL
- **Principal Investigator:** CRAIG THOMAS LEFORT
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $402,500
- **Award type:** 5
- **Project period:** 2017-08-05 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9985612

## Citation

> US National Institutes of Health, RePORTER application 9985612, Selective modulation of neutrophils in critical illness (5R35GM124911-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9985612. Licensed CC0.

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