Iron metabolism at the host pathogen interface: Lipocalin 2 and the pathogen-associated iroA gene cluster

Smith, Kelly D.

doi:10.1016/j.biocel.2007.07.003

Cited by 53 publications

(46 citation statements)

References 28 publications

(34 reference statements)

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“…24 Similarly, lipocalin-2 is an iron-binding protein that is upregulated by inflammation and may help sequester iron during infections. 49 It is produced by adipose tissue and its expression is increased in db/db (leptin receptor-deficient) obese mice. 50 Thus, low iron status in overweight individuals could result from a combination of nutritional (reduced absorption) and functional (increased sequestration) iron deficiency.…”

Section: Discussionmentioning

confidence: 99%

Adiposity in women and children from transition countries predicts decreased iron absorption, iron deficiency and a reduced response to iron fortification

et al. 2008

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Background: Overweight is increasing in transition countries, while iron deficiency remains common. In industrialized countries, greater adiposity increases risk of iron deficiency. Higher hepcidin levels in obesity may reduce dietary iron absorption. Therefore, we investigated the association between body mass index (BMI) and iron absorption, iron status and the response to iron fortification in populations from three transition countries (Thailand, Morocco and India). Methods: In Thai women (n ¼ 92), we examined the relationship between BMI and iron absorption from a reference meal containing B4 mg of isotopically labeled fortification iron. We analyzed data from baseline (n ¼ 1688) and intervention (n ¼ 727) studies in children in Morocco and India to look for associations between BMI Z-scores and baseline hemoglobin, serum ferritin and transferrin receptor, whole blood zinc protoporphyrin and body iron stores, and changes in these measures after provision of iron. Results: In the Thai women, 20% were iron deficient and 22% were overweight. Independent of iron status, a higher BMI Z-score was associated with decreased iron absorption (P ¼ 0.030). In the Indian and Moroccan children, 42% were iron deficient and 6.3% were overweight. A higher BMI Z-score predicted poorer iron status at baseline (Po0.001) and less improvement in iron status during the interventions (Po0.001). Conclusions: Adiposity in young women predicts lower iron absorption, and pediatric adiposity predicts iron deficiency and a reduced response to iron fortification. These data suggest the current surge in overweight in transition countries may impair efforts to control iron deficiency in these target groups. Interactions of the 'double burden' of malnutrition during the nutrition transition may have adverse consequences.

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Section: Discussionmentioning

confidence: 99%

Adiposity in women and children from transition countries predicts decreased iron absorption, iron deficiency and a reduced response to iron fortification

et al. 2008

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“…Not surprisingly, UPEC has evolved a mechanism to counter Lcn2 siderophore sequestration. Encoded within the iroA gene cluster are glycosyltransferases that modify enterobactin in such a way that it cannot be bound by Lcn2 (30,71,239). Thus, both the host and UPEC have systems in place to manage their own iron stores and to inhibit iron acquisition by the other-a molecular arms race for an essential nutrient.…”

Section: Hand-to-hand Combat: Battle For Precious Resourcesmentioning

confidence: 99%

Waging War against UropathogenicEscherichia coli: Winning Back the Urinary Tract

2010

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Urinary tract infection (UTI) caused by uropathogenic Escherichia coli (UPEC) is a substantial economic and societal burden-a formidable public health issue. Symptomatic UTI causes significant discomfort in infected patients, results in lost productivity, predisposes individuals to more serious infections, and usually necessitates antibiotic therapy. There is no licensed vaccine available for prevention of UTI in humans in the United States, likely due to the challenge of targeting a relatively heterogeneous group of pathogenic strains in a unique physiological niche. Despite significant advances in the understanding of UPEC biology, mechanistic details regarding the host response to UTI and full comprehension of genetic loci that influence susceptibility require additional work. Currently, there is an appreciation for the role of classic innate immune responses-from pattern receptor recognition to recruitment of phagocytic cells-that occur during UPEC-mediated UTI. There is, however, a clear disconnect regarding how factors involved in the innate immune response to UPEC stimulate acquired immunity that facilitates enhanced clearance upon reinfection. Unraveling the molecular details of this process is vital in the development of a successful vaccine for prevention of human UTI. Here, we survey the current understanding of host responses to UPEC-mediated UTI with an eye on molecular and cellular factors whose activity may be harnessed by a vaccine that stimulates lasting and sterilizing immunity. MISSION: ERADICATE UPEC-MEDIATED UTIUrinary tract infection (UTI) is one of the most common infections in humans. Bacteria present in fecal matter inoculate the periurethral area, then the bladder (124, 176, 291), causing symptoms clinically termed cystitis. Left untreated, bacteria ascend the ureters to the kidney and establish a secondary infection, acute pyelonephritis. At this juncture, there is risk of permanent renal scarring, and bacteria can access the bloodstream (282). It is estimated that 40% of women and 12% of men will experience a symptomatic UTI, with incidences peaking in their early 20s or after age 85, respectively (75, 185). Approximately 25% of these women will experience recurrence within 6 to 12 months (75, 185). Uropathogenic Escherichia coli (UPEC) is the most common etiological agent responsible for uncomplicated UTI (93, 94,282). Uropathogenic strains are classified as extraintestinal pathogenic E. coli, a broad grouping of E. coli that cause diseases other than gastroenteritis and typically lack a type III secretion system (171,220,221,283,284). Nonetheless, UPEC strains express an assortment of virulence and fitness factors that aid in successful colonization of the mammalian urinary tract (126,136). In the United States alone, the estimated annual societal cost of UTI is more than 3 billion dollars (159).Despite a relatively in-depth knowledge base for UPEC physiology and virulence mechanisms (reviewed in references 54, 126, 136, and 284), no licensed vaccine to prevent UTI exists in the Un...

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“…Accordingly, mice deficient in Lcn2 are highly susceptible to infection with E. coli (22,23). Thus, Lcn2 mediates the host defense against E. coli infection through sequestration of iron, which is essential for the growth and activity of nearly all bacteria (24).…”

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confidence: 99%

Lipocalin 2-Dependent Inhibition of Mycobacterial Growth in Alveolar Epithelium

Saiga

Nishimura

Kuwata

et al. 2008

The Journal of Immunology

127

130

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Mycobacterium tuberculosis invades alveolar epithelial cells as well as macrophages. However, the role of alveolar epithelial cells in the host defense against M. tuberculosis remains unknown. In this study, we report that lipocalin 2 (Lcn2)-dependent inhibition of mycobacterial growth within epithelial cells is required for anti-mycobacterial innate immune responses. Lcn2 is secreted into the alveolar space by alveolar macrophages and epithelial cells during the early phase of respiratory mycobacterial infection. Lcn2 inhibits the in vitro growth of mycobacteria through sequestration of iron uptake. Lcn2-deficient mice are highly susceptible to intratracheal infection with M. tuberculosis. Histological analyses at the early phase of mycobacterial infection in Lcn2-deficient mice reveal increased numbers of mycobacteria in epithelial cell layers, but not in macrophages, in the lungs. Increased intracellular mycobacterial growth is observed in alveolar epithelial cells, but not in alveolar macrophages, from Lcn2-deficient mice. The inhibitory action of Lcn2 is blocked by the addition of endocytosis inhibitors, suggesting that internalization of Lcn2 into the epithelial cells is a prerequisite for the inhibition of intracellular mycobacterial growth. Taken together, these findings highlight a pivotal role for alveolar epithelial cells during mycobacterial infection, in which Lcn2 mediates anti-mycobacterial innate immune responses within the epithelial cells.

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Iron metabolism at the host pathogen interface: Lipocalin 2 and the pathogen-associated iroA gene cluster

Cited by 53 publications

References 28 publications

Adiposity in women and children from transition countries predicts decreased iron absorption, iron deficiency and a reduced response to iron fortification

Adiposity in women and children from transition countries predicts decreased iron absorption, iron deficiency and a reduced response to iron fortification

Waging War against UropathogenicEscherichia coli: Winning Back the Urinary Tract

Lipocalin 2-Dependent Inhibition of Mycobacterial Growth in Alveolar Epithelium

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