# Mechanisms Of Impaired Macrophage Function in Lung Injury - Project 4

> **NIH NIH P01** · OHIO STATE UNIVERSITY · 2022 · $367,384

## Abstract

Project Summary/Abstract: The broad, long-term objective of this Project is to better understand the
underlying mechanisms of immunosuppression following infection in the lungs by examining distinct host-
pathogen interplay. Severe acute lower respiratory tract infection or pneumonia remains a major cause of
sepsis and risk factor for the acute respiratory distress syndrome (ARDS) worldwide. However, bacterial
pneumonia is also a frequent complication of ARDS and prolonged mechanical ventilation that increases
patient morbidity, length of stay, and health-care costs. Yet, many aspects of host-pathogen interactions
remain poorly understood and the underlying defects in host control mechanisms that occur during critical
illness remain outstanding questions in ARDS. We have developed a 2-hit murine model targeting the
mononuclear phagocyte system of the liver to study the consequences of severe lung infection induced by
Klebsiella pneumoniae, an extracellular Gram-negative pathogen that is a common cause of nosocomial
pneumonia, and potential link to systemic immunosuppression. We identified impaired expression of interferon-
regulatory factor 1 (IRF-1), a transcription factor critical for boosting antimicrobial and antiviral innate immunity,
in this 2-hit model leading us to propose that defects in IRF-1 mediates the immunosuppressive phenotype by
impairing transactivation of key innate immunity genes important for host defense. Moreover, preliminary
findings suggest that a proportion of critically ill patients exhibit an immunosuppressive phenotype
characterized by failure to control relatively avirulent carbapenamase-producing Klebsiella pneumoniae (KP)
growth in vitro, and impaired serum killing of KP is associated with defects in alternative but not classical
complement activity. Most complement proteins are synthesized in the liver, but macrophages/monocytes also
synthesize these factors, many of which are regulated by interferons. Collectively, preliminary findings from the
2-hit model and patient serum have led us to propose a major hypothesis that macrophage dysfunction
characterized by defects in IRF-1 marks the host for an immunosuppressive fate during infection due to
impaired cytokine response, microbial killing, and complement activity. Aim 1 will determine whether
impairment in IRF-1 signaling is a mechanism for defective chemokine and cytokine response in
the 2-hit model. Aim 2 will evaluate whether defects in mitochondrial aconitate decarboxylase 1 (ACOD1)
downstream of IRF-1 impairs host anti-microbial program during KP infection and in the 2-hit model. Aim 3 will
evaluate IRF-1 activation, the dynamics of alternative pathway complement factors synthesized by
mononuclear phagocytes, and relationship to AP activity in a cohort of critically ill patients. Successful
completion of the aims will elucidate novel mechanisms of host control and aid in the long-term objective of
understanding immunosuppressive signals complicating severe p...

## Key facts

- **NIH application ID:** 10399562
- **Project number:** 5P01HL114453-09
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Janet Sojung Lee
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $367,384
- **Award type:** 5
- **Project period:** 2014-01-03 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10399562

## Citation

> US National Institutes of Health, RePORTER application 10399562, Mechanisms Of Impaired Macrophage Function in Lung Injury - Project 4 (5P01HL114453-09). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10399562. Licensed CC0.

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