Salmonella Mitigates Oxidative Stress and Thrives in the Inflamed Gut by Evading Calprotectin-Mediated Manganese Sequestration.
Neutrophils hinder bacterial growth by a variety of antimicrobial mechanisms, including the production of reactive oxygen species and the secretion of proteins that sequester nutrients essential to microbes. A major player in this process is calprotectin, a host protein that exerts antimicrobial activity by chelating zinc and manganese. Here we show that the intestinal pathogen Salmonella enterica serovar Typhimurium uses specialized metal transporters to evade calprotectin sequestration of manganese, allowing the bacteria to outcompete commensals and thrive in the inflamed gut. The pathogen's ability to acquire manganese in turn promotes function of SodA and KatN, enzymes that use the metal as a cofactor to detoxify reactive oxygen species. This manganese-dependent SodA activity allows the bacteria to evade neutrophil killing mediated by calprotectin and reactive oxygen species. Thus, manganese acquisition enables S. Typhimurium to overcome host antimicrobial defenses and support its competitive growth in the intestine.
Department of Microbiology and Molecular Genetics, University of California, Irvine, Irvine, CA 92697-4025, USA; Institute for Immunology, University of California, Irvine, Irvine, CA 92697-4120, USA.
Vladimir E
VE
Diaz-Ochoa
Department of Microbiology and Molecular Genetics, University of California, Irvine, Irvine, CA 92697-4025, USA; Institute for Immunology, University of California, Irvine, Irvine, CA 92697-4120, USA.
Diana
D
Lam
Department of Microbiology and Molecular Genetics, University of California, Irvine, Irvine, CA 92697-4025, USA; Institute for Immunology, University of California, Irvine, Irvine, CA 92697-4120, USA.
Carlin S
CS
Lee
Department of Microbiology and Molecular Genetics, University of California, Irvine, Irvine, CA 92697-4025, USA; Institute for Immunology, University of California, Irvine, Irvine, CA 92697-4120, USA.
Suzi
S
Klaus
Department of Microbiology and Molecular Genetics, University of California, Irvine, Irvine, CA 92697-4025, USA; Institute for Immunology, University of California, Irvine, Irvine, CA 92697-4120, USA.
Judith
J
Behnsen
Department of Microbiology and Molecular Genetics, University of California, Irvine, Irvine, CA 92697-4025, USA; Institute for Immunology, University of California, Irvine, Irvine, CA 92697-4120, USA.
Janet Z
JZ
Liu
Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA 92697-3900, USA.
Nicholas
N
Chim
Department of Microbiology and Molecular Genetics, University of California, Irvine, Irvine, CA 92697-4025, USA; Institute for Immunology, University of California, Irvine, Irvine, CA 92697-4120, USA.
Sean-Paul
SP
Nuccio
Department of Biochemistry and Chemistry, Vanderbilt University, Nashville, TN 37232-8725, USA.
Subodh G
SG
Rathi
Department of Pathology and Laboratory Medicine, University of Southern California, Los Angeles, CA 90089-9092, USA.
Jennifer R
JR
Mastroianni
Department of Pathology and Laboratory Medicine, University of California, Irvine, Irvine, CA 92697-4800, USA.
Robert A
RA
Edwards
Department of Microbiology and Molecular Genetics, University of California, Irvine, Irvine, CA 92697-4025, USA; Institute for Immunology, University of California, Irvine, Irvine, CA 92697-4120, USA.
Christina M
CM
Jacobo
Department of Biology, University of Rome, Tor Vergata, 00173 Roma, Italy.
Mauro
M
Cerasi
Department of Biology, University of Rome, Tor Vergata, 00173 Roma, Italy.
Andrea
A
Battistoni
Department of Pathology and Laboratory Medicine, University of Southern California, Los Angeles, CA 90089-9092, USA.
André J
AJ
Ouellette
Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA 92697-3900, USA; Department of Pharmaceutical Sciences, University of California, Irvine, Irvine, CA 92697-3958, USA.
Celia W
CW
Goulding
Department of Biochemistry and Chemistry, Vanderbilt University, Nashville, TN 37232-8725, USA.
Walter J
WJ
Chazin
Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232-2363, USA; Tennessee Valley Healthcare System, US Department of Veterans Affairs, Nashville, TN 37212, USA.
Eric P
EP
Skaar
Department of Microbiology and Molecular Genetics, University of California, Irvine, Irvine, CA 92697-4025, USA; Institute for Immunology, University of California, Irvine, Irvine, CA 92697-4120, USA. Electronic address: manuelar@uci.edu.
Manuela
M
Raffatellu
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000975:Antioxidants / Q000378:metabolism; D001426:Bacterial Proteins / Q000378:metabolism; D002614:Chelating Agents / Q000494:pharmacology; D004926:Escherichia coli / Q000254:growth & development / Q000502:physiology; D005759:Gastroenteritis / Q000188:drug therapy / Q000378:metabolism / Q000382:microbiology*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000382:microbiology*; D039841:Leukocyte L1 Antigen Complex / Q000494:pharmacology*; D008345:Manganese / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012480:Salmonella Infections / Q000188:drug therapy / Q000378:metabolism / Q000382:microbiology; D012486:Salmonella typhimurium / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development / Q000502:physiology*; D013559:Symbiosis; D015032:Zinc / Q000378:metabolism
D000900:Anti-Bacterial Agents; D000975:Antioxidants; D001426:Bacterial Proteins; D002614:Chelating Agents; D039841:Leukocyte L1 Antigen Complex; D017382:Reactive Oxygen Species; D008345:Manganese; D015032:Zinc