Zinc Sequestration by the Neutrophil Protein Calprotectin Enhances Salmonella Growth in the Inflamed Gut
Open accessAbstract
Neutrophils are innate immune cells that counter pathogens by many mechanisms, including release of antimicrobial proteins such as calprotectin to inhibit bacterial growth. Calprotectin sequesters essential micronutrient metals such as zinc, thereby limiting their availability to microbes, a process termed nutritional immunity. We find that while calprotectin is induced by neutrophils during infection with the gut pathogen Salmonella Typhimurium, calprotectin-mediated metal sequestration does not inhibit S. Typhimurium proliferation. Remarkably, S. Typhimurium overcomes calprotectin-mediated zinc chelation by expressing a high affinity zinc transporter (ZnuABC). A S. Typhimurium znuA mutant impaired for growth in the inflamed gut was rescued in the absence of calprotectin. ZnuABC was also required to promote the growth of S. Typhimurium over that of competing commensal bacteria. Thus, our findings indicate that Salmonella thrives in the inflamed gut by overcoming the zinc sequestration of calprotectin and highlight the importance of zinc acquisition in bacterial intestinal colonization.
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Metal depletion strategies of the host affect pathogenic bacteria and commensal/protective flora, and bacteria that evolved strategies to outcompete metal restrictions benefit and may become more pathogenic.
“However metal depletion strategies of the host not only affect pathogenic bacteria but also the commensal/protective flora, and thus bacteria that have evolved strategies to outcompete these metal restrictions benefit from a developmental advantage and may become more pathogenic (240).”
From Macrophage defense mechanisms against intracellular bacteria (2015) · cites this paper as [240]
Zinc plays central roles for the function of structural proteins and is essential for immune cell proliferation and differentiation.
“The transition metal zinc plays central roles for the function of structural proteins and is essential for immune cell proliferation and differentiation (240).”
From Macrophage defense mechanisms against intracellular bacteria (2015) · cites this paper as [240]
Calprotectin enhances S. enterica growth in the inflamed gut, presumably because S. enterica can outcompete the gut microbiota for limited zinc.
“Calprotectin enhances S. enterica growth in the inflamed gut, presumably because S. enterica can outcompete the gut microbiota for limited zinc (79).”
From Transition Metals and Virulence in Bacteria (2016) · cites this paper as [79]
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Self-citation
- Authors
- Liu, J. Z., Jellbauer, S., Poe, A. J., Ton, V., Pesciaroli, M., Kehl-Fie, T. E., Restrepo, N. A., Hosking, M. P., Edwards, R. A., Battistoni, A., Pasquali, P., Lane, T. E., Chazin, W. J., Vogl, T., Roth, J., Skaar, E. P., & Raffatellu, M.
- Affiliations
- University of California, Irvine (US)
- Vanderbilt University (US)
- University of Rome Tor Vergata (IT)
- Istituto Superiore di Sanità (IT)
- University of Münster (DE)
- Corresponding author
- Raffatellu, Manuela
- ORCID
- Venue
- Cell Host & Microbe
- Publisher
- Elsevier BV
- Published
- 2012-03
- Volume
- 11
- Issue
- 3
- Pages
- 227-239
- ISSN
- 1931-3128 (ISSN-L)
- PMC
- PMC3308348
- OpenAlex
- W2039176236
- Cited by
- 328
- References
- 50
- Citations by year
- 2026: 13 · 2025: 23 · 2024: 11 · 2023: 15 · 2022: 21 · 2021: 25 · 2020: 21 · 2019: 20 · 2018: 21 · 2017: 26 · 2016: 29 · 2015: 32 · 2014: 30 · 2013: 26 · 2012: 15
- FWCI
- 50.66
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 539 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell Host & Microbe (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Cineca Institutional Research Information System (Tor Vergata University) (submittedVersion, cc-by-nc-nd)
- Funders
- National Cancer Institute (P30CA062203)
- National Institute of General Medical Sciences (R01GM062112, GM62112-08S1)
- National Institute of Allergy and Infectious Diseases (AI083663, AI083619, T32 AI60573, AI073843, AI091771, R01AI083663, R21AI083619, T32AI060573, R56AI091771, R01AI073843)
- National Institute of Neurological Disorders and Stroke (R01NS041249, NS 041249)
- Topics
- Life Sciences › Agricultural and Biological Sciences › Food Science › Salmonella and Campylobacter epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › S100 Proteins and Annexins
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Keywords
- calprotectin, zinc sequestration, Salmonella typhimurium, nutritional immunity, neutrophils, intestinal inflammation, intestinal colonization, innate immunity
- MeSH terms
- Animals, Bacterial Proteins, Cecum, Diarrhea, Feces, Immunity, Innate, Inflammation, Mice, Inbred C57BL, Neutrophils, Protein Binding, Salmonella Infections, Animal, Salmonella typhimurium, Transcription, Genetic, Zinc, Mice, Knockout, ATP-Binding Cassette Transporters, Leukocyte L1 Antigen Complex, Mice, Host-Pathogen Interactions
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