# Heme-mediated STAT1 Dysfunction in Macrophages During Klebsiella pneumoniae Lung Infection

> **NIH NIH F31** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $46,752

## Abstract

PROJECT SUMMARY/ABSTRACT
 Macrophages are key effector immune cells in host defense against pathogen invasion, and
understanding factors that cause macrophage dysfunction during severe infection remains a high priority in
biomedical research. An acute rise in red blood cell engulfment by macrophages, called stressed
erythrophagocytosis, occurs in pathologic conditions such as transfusion heme-iron overload, anemia of
inflammation, certain hemolytic anemias, or severe sepsis, and involves the uptake of excess senescent red
cells (sRBCs). Using a two-hit model of red cell transfusion and acute pulmonary infection, we recently uncovered
a mechanism whereby stressed erythrophagocytosis led to a state of immunosuppression following Klebsiella
pneumoniae (KP) infection in mice. This state of immunosuppression arose from a disruption in interferon
signaling in the liver during infection, was caused by excess heme handling by macrophages, and led to a
deficiency of STAT1, a master regulator of interferon responses. We previously established an experimental
system in which macrophages are exposed to KP infection and concomitant sRBC delivery or excess hemin in
vitro. In addition, we have developed a well-established bacterial pneumonia model system using KP that will be
combined with direct delivery of sRBC or heme to the lung in order to examine alterations in macrophage
phenotype and the immune cell repertoire in vivo. This proposal will test the hypothesis that excess heme in the
lung, such as in conditions of local tissue damage during severe infection, can induce a state of STAT1-deficiency
in macrophages, in part, by impairing STAT1 protein stability with deleterious consequences on host defense.
Utilizing in vitro and in vivo model systems, I propose to investigate this hypothesis by pursuing the following
aims: Aim 1. Determine whether excess heme induces a state of STAT1 deficiency in macrophages during KP
infection by impairing STAT1 protein stability in vitro. Aim 2. Examine whether excess heme alters macrophage
phenotype in the lung and impairs effective host defense during KP infection in vivo. Successful completion of
this project will provide novel information regarding host-pathogen interactions during pathologic conditions of
excess heme, and will address a gap in understanding of dysregulated host response in the lung during severe
respiratory infection.

## Key facts

- **NIH application ID:** 10534918
- **Project number:** 1F31HL165732-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Shekina Gonzalez-Ferrer
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $46,752
- **Award type:** 1
- **Project period:** 2022-08-05 → 2025-08-04

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10534918

## Citation

> US National Institutes of Health, RePORTER application 10534918, Heme-mediated STAT1 Dysfunction in Macrophages During Klebsiella pneumoniae Lung Infection (1F31HL165732-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10534918. Licensed CC0.

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