# Metallobiochemistry of innate immunity and bacterial physiology

> **NIH NIH R01** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2020 · $271,261

## Abstract

PROJECT SUMMARY
The primary objective of this research initiative is to evaluate how the metal-sequestering human host-defense
protein calprotectin (CP) affects metal homeostasis and physiology of bacterial pathogens. Metal ions are
essential nutrients for all organisms, and pathogens must acquire these nutrients from the host to replicate and
cause infection. During this process, the human innate immune system works to limit the bioavailability of
transition metals including manganese (Mn), iron (Fe), and zinc (Zn) by deploying CP and other metal-
sequestering proteins at sites of infection. CP is accepted to withhold Mn(II) and Zn(II) from microbial
pathogens, and we recently demonstrated that CP coordinates Fe in the reduced ferrous oxidation state.
Bacterial systems for Fe(II) acquisition are increasingly appreciated as critical for pathogenesis in multiple
infection states, including chronic, biofilm-mediated infections where oxygen becomes limiting. However, no
other host-defense proteins that limit Fe(II) have been identified; thus investigating CP as an Fe(II)-
sequestering host-defense protein is important for understanding host-pathogen interactions in chronic
infection states. Pseudomonas aeruginosa (Pa) and Staphylococcus aureus (Sa) are two human pathogens
that cause chronic polymicrobial infections in diverse patient populations, including lung infections in
individuals with cystic fibrosis (CF). This hereditary disease predisposes individuals to life-long pulmonary
infections, marked by debilitating exacerbations that reduce lung function. Notably, the CF lung becomes
increasingly hypoxic as disease progresses, and multiple lines of evidence indicate that Fe(II) becomes the
predominant form of bioavailable Fe. Progression of CF lung disease is also correlated with a shift in microbial
etiology, with Sa being the predominant microorganism in younger patients, and subsequent Pa colonization
associated with lung function decline. The underlying biology that causes this population shift remains poorly
understood; however, recent studies suggest that both Fe and CP contribute to this process. We hypothesize
that CP limits Fe(II) availability in hypoxic environments, as found in the CF lung, and that this activity
eventually allows Pa to outcompete Sa in polymicrobial environments. In Aim 1, we will evaluate Fe(II)
sequestration by CP, and map the distribution of metal ions in Pa and Sa cultures treated with CP. In Aim 2,
we will test the hypothesis that CP limits Fe(II) to Pa and Sa, and thereby impacts the individual physiologies
and co-culture dynamics of these two pathogens. These investigations will enable future studies that address
how CP and Fe drive the progression of CF lung infections, and may guide the design and development of
novel diagnostic, preventative, and therapeutic approaches to treat bacterial infections.

## Key facts

- **NIH application ID:** 9994757
- **Project number:** 5R01GM126376-04
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** ELIZABETH M NOLAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $271,261
- **Award type:** 5
- **Project period:** 2017-09-20 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9994757

## Citation

> US National Institutes of Health, RePORTER application 9994757, Metallobiochemistry of innate immunity and bacterial physiology (5R01GM126376-04). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9994757. Licensed CC0.

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