Salmonella Mitigates Oxidative Stress and Thrives in the Inflamed Gut by Evading Calprotectin-Mediated Manganese Sequestration

Diaz-Ochoa, Vladimir E.; Lam, Diana; Lee, Carlin; Klaus, Suzi; Behnsen, Judith; Liu, Janet Z.; Chim, Nicholas; Nuccio, Sean Paul; Rathi, Subodh; Mastroianni, Jennifer R.; Edwards, Robert A.; Jacobo, Christina M.; Cerasi, Mauro; Battistoni, Andrea; Ouellette, André J.; Goulding, Celia W.; Chazin, Walter J.; Skaar, Eric P.; Raffatellu, Manuela

doi:10.1016/j.chom.2016.05.005

Cited by 121 publications

(136 citation statements)

References 67 publications

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“…With this response to CP, C. albicans maintains constant intracellular Zn over numerous cell divisions despite virtually undetectable bioavailable Zn outside the cell. Similar findings with Zn transporters and CP have been reported for the fungal pathogen A. fumigatus (17,18), and upregulation of transition metal import genes is also an effective strategy against CP in bacterial pathogens including Acinetobacter baumannii, S. aureus, and Salmonella (14,16,20,65,66). Aside from Zn, we demonstrate for the first time that CP can withhold Cu from a microbial organism by virtue of its picomolar affinity for Cu(II).…”

Section: Discussionsupporting

confidence: 86%

Role of Calprotectin in Withholding Zinc and Copper from Candida albicans

et al. 2018

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The opportunistic fungal pathogen Candida albicans acquires essential metals from the host, yet the host can sequester these micronutrients through a process known as nutritional immunity. How the host withholds metals from C. albicans has been poorly understood; here we examine the role of calprotectin (CP), a transition metal binding protein. When CP depletes bioavailable Zn from the extracellular environment, C. albicans strongly upregulates ZRT1 and PRA1 for Zn import and maintains constant intracellular Zn through numerous cell divisions. We show for the first time that CP can also sequester Cu by binding Cu(II) with subpicomolar affinity. CP blocks fungal acquisition of Cu from serum and induces a Cu starvation stress response involving SOD1 and SOD3 superoxide dismutases. These transcriptional changes are mirrored when C. albicans invades kidneys in a mouse model of disseminated candidiasis, although the responses to Cu and Zn limitations are temporally distinct. The Cu response progresses throughout 72 h, while the Zn response is short-lived. Notably, these stress responses were attenuated in CP null mice, but only at initial stages of infection. Thus, Zn and Cu pools are dynamic at the hostpathogen interface and CP acts early in infection to restrict metal nutrients from C. albicans.

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Section: Discussionsupporting

confidence: 86%

Role of Calprotectin in Withholding Zinc and Copper from Candida albicans

et al. 2018

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“…In line with a model of tissue-specific Mn sequestration by calprotectin, staphylococcal kidney lesions are devoid of Mn even in S100a9 −/− mice (Kehl-Fie et al,. 2013), and calprotectin does not impact Mn bioavailability to Salmonella during gastrointestinal infection (Diaz-Ochoa et al, 2016). These findings raise the possibility that additional mechanisms exist to regulate the metal-sequestering properties of antimicrobial proteins in a tissue- or context- dependent fashion.…”

Section: Discussionmentioning

confidence: 99%

“…Consistent with this, calprotectin-deficient mice systemically infected with S. aureus have increased Mn levels in liver lesions (Corbin et al, 2008). However, calprotectin-deficiency does not significantly impact the fitness of Salmonella strains lacking Mn import systems in a gastrointestinal infection model (Diaz-Ochoa et al, 2016), suggesting that calprotectin-dependent Mn sequestration may be restricted to certain tissues.…”

Section: Introductionmentioning

confidence: 99%

Dietary Manganese Promotes Staphylococcal Infection of the Heart

Juttukonda

Berends

Zackular

et al. 2017

Cell Host & Microbe

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Summary Diet and specifically dietary metals can modify the risk of infection. However, the mechanisms by which manganese (Mn), a common dietary supplement, alters infection remain unexplored. We report that dietary Mn levels dictate the outcome of systemic infections caused by Staphylococcus aureus, a leading cause of bacterial endocarditis. Mice fed a high Mn diet display alterations in Mn levels and localization within infected tissues, and S. aureus virulence and infection of the heart are enhanced. Although the canonical mammalian Mn-sequestering protein calprotectin surrounds staphylococcal heart abscesses, calprotectin is not released into the abscess nidus and does not limit Mn in this organ. Consequently, excess Mn is bioavailable to S. aureus in the heart. Bioavailable Mn is utilized by S. aureus to detoxify reactive oxygen species and protect against neutrophil killing, enhancing fitness within the heart. Therefore, a single dietary modification overwhelms vital host antimicrobial strategies, leading to fatal staphylococcal infection.

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“…Indeed, Mn ++ uptake promotes S . Typhimurim survival in the inflamed gut in a mouse model for enterocolitis [51]. …”

Section: Detoxification Of Rosmentioning

confidence: 99%

<b><i>Salmonella</i></b> and Reactive Oxygen Species: A Love-Hate Relationship

Rhen¹

2019

J Innate Immun

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Salmonella enterica represents an enterobacterial species including numerous serovars that cause infections at, or initiated at, the intestinal epithelium. Many serovars also act as facultative intracellular pathogens with a tropism for phagocytic cells. These bacteria not only survive in phagocytes but also undergo de facto replication therein. Phagocytes, through the activities of phagocyte NADPH-dependent oxidase and inducible nitric oxide synthase, are very proficient in converting molecular oxygen to reactive oxygen (ROS) and nitrogen species (RNS). These compounds represent highly efficient effectors of the innate immune defense. Salmonella is by no means resistant to these effectors, which may stand in contrast to the host niches chosen. To cope with this paradox, these bacteria rely on an array of detoxification and repair systems. Combination these systems allows for a high enough tolerance to ROS and RNS to enable establishment of infection. In addition, salmonella possesses protein factors that have the potential to dampen the infection-associated inflammation, which evidently results in a reduced exposure to ROS and RNS. This review attempts to summarize the activities and strategies by which salmonella tries to cope with ROS and RNS and how the bacterium can make use of these innate defense factors.

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Salmonella Mitigates Oxidative Stress and Thrives in the Inflamed Gut by Evading Calprotectin-Mediated Manganese Sequestration

Cited by 121 publications

References 67 publications

Role of Calprotectin in Withholding Zinc and Copper from Candida albicans

Role of Calprotectin in Withholding Zinc and Copper from Candida albicans

Dietary Manganese Promotes Staphylococcal Infection of the Heart

<b><i>Salmonella</i></b> and Reactive Oxygen Species: A Love-Hate Relationship

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