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Research Article | Host-Microbe Biology

The Immune Protein Calprotectin Impacts Clostridioides difficile Metabolism through Zinc Limitation

Christopher A. Lopez, William N. Beavers, Andy Weiss, Reece J. Knippel, Joseph P. Zackular, Walter Chazin, Eric P. Skaar
Robert A. Britton, Invited Editor, Kimberly A. Kline, Editor
Christopher A. Lopez
aDepartment of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
bVanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, Tennessee, USA
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William N. Beavers
aDepartment of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
bVanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, Tennessee, USA
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Andy Weiss
aDepartment of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
bVanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, Tennessee, USA
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Reece J. Knippel
aDepartment of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
bVanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, Tennessee, USA
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Joseph P. Zackular
cDepartment of Pathology and Laboratory Medicine, Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
gDivision of Protective Immunity, Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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Walter Chazin
dDepartment of Chemistry, Vanderbilt University, Nashville, Tennessee, USA
eDepartment of Biochemistry, Vanderbilt University, Nashville, Tennessee, USA
fCenter for Structural Biology, Vanderbilt University, Nashville, Tennessee, USA
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Eric P. Skaar
aDepartment of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
bVanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, Tennessee, USA
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Robert A. Britton
Baylor College of Medicine
Roles: Invited Editor
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Kimberly A. Kline
Nanyang Technological University
Roles: Editor
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DOI: 10.1128/mBio.02289-19
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ABSTRACT

The intestines house a diverse microbiota that must compete for nutrients to survive, but the specific limiting nutrients that control pathogen colonization are not clearly defined. Clostridioides difficile colonization typically requires prior disruption of the microbiota, suggesting that outcompeting commensals for resources is critical to establishing C. difficile infection (CDI). The immune protein calprotectin (CP) is released into the gut lumen during CDI to chelate zinc (Zn) and other essential nutrient metals. Yet, the impact of Zn limitation on C. difficile colonization is unknown. To define C. difficile responses to Zn limitation, we performed RNA sequencing on C. difficile exposed to CP. In medium containing CP, C. difficile upregulated genes involved in metal homeostasis and amino acid metabolism. To identify CP-responsive genes important during infection, we measured the abundance of select C. difficile transcripts in a mouse CDI model relative to expression in vitro. Gene transcripts involved in selenium (Se)-dependent proline fermentation increased during infection and in response to CP. Increased proline fermentation gene transcription was dependent on CP Zn binding and proline availability, yet proline fermentation was only enhanced when Se was supplemented. CP-deficient mice could not restrain C. difficile proline fermentation-dependent growth, suggesting that CP-mediated Zn sequestration along with limited Se restricts C. difficile proline fermentation. Overall, these results highlight how C. difficile colonization depends on the availability of multiple nutrients whose abundances are dynamically influenced by the host response.

IMPORTANCE Clostridioides difficile infection (CDI) is the leading cause of postantibiotic nosocomial infection. Antibiotic therapy can be successful, yet up to one-third of individuals suffer from recurrent infections. Understanding the mechanisms controlling C. difficile colonization is paramount in designing novel treatments for primary and recurrent CDI. Here, we found that limiting nutrients control C. difficile metabolism during CDI and influence overall pathogen fitness. Specifically, the immune protein CP limits Zn availability and increases transcription of C. difficile genes necessary for proline fermentation. Paradoxically, this leads to reduced C. difficile proline fermentation. This reduced fermentation is due to limited availability of another nutrient required for proline fermentation, Se. Therefore, CP-mediated Zn limitation combined with low Se levels overall reduce C. difficile fitness in the intestines. These results emphasize the complexities of how nutrient availability influences C. difficile colonization and provide insight into critical metabolic processes that drive the pathogen’s growth.

  • Copyright © 2019 Lopez et al.

This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

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The Immune Protein Calprotectin Impacts Clostridioides difficile Metabolism through Zinc Limitation
Christopher A. Lopez, William N. Beavers, Andy Weiss, Reece J. Knippel, Joseph P. Zackular, Walter Chazin, Eric P. Skaar
mBio Nov 2019, 10 (6) e02289-19; DOI: 10.1128/mBio.02289-19

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The Immune Protein Calprotectin Impacts Clostridioides difficile Metabolism through Zinc Limitation
Christopher A. Lopez, William N. Beavers, Andy Weiss, Reece J. Knippel, Joseph P. Zackular, Walter Chazin, Eric P. Skaar
mBio Nov 2019, 10 (6) e02289-19; DOI: 10.1128/mBio.02289-19
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KEYWORDS

Clostridioides difficile
Stickland fermentation
calprotectin
proline
zinc

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