Impact of Aging on Urinary Excretion of Iron and Zinc

Pfrimer, Karina; Micheletto, Rutinéia Fátima; Marchini, Júlio Sérgio; Padovan, Gilberto João; Moriguti, Júlio C.; Ferriolli, Eduardo

doi:10.4137/nmi.s12977

Cited by 12 publications

(9 citation statements)

References 17 publications

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“…54,[61][62][63] Similarly, postmenopausal women who are highly susceptible to multiple recurrent and chronic UTIs have been shown to carry higher than normal levels of iron in their urine. 61,64,65 Given our findings that even at physiological levels of iron (25 mM) we observe increased and prolonged bacterial burden, our data shows that even slightly augmented levels can be beneficial for UPEC persistence. Together, our data support the model (illustrated in Fig.…”

Section: Discussionsupporting

confidence: 50%

Ferritinophagy drives uropathogenicEscherichia colipersistence in bladder epithelial cells

Bauckman

Mysorekar

2016

Autophagy

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Autophagy is a cellular recycling pathway, which in many cases, protects host cells from infections by degrading pathogens. However, uropathogenic Escherichia coli (UPEC), the predominant cause of urinary tract infections (UTIs), persist within the urinary tract epithelium (urothelium) by forming reservoirs within autophagosomes. Iron is a critical nutrient for both host and pathogen, and regulation of iron availability is a key host defense against pathogens. Iron homeostasis depends on the shuttling of iron-bound ferritin to the lysosome for recycling, a process termed ferritinophagy (a form of selective autophagy). Here, we demonstrate for the first time that UPEC shuttles with ferritin-bound iron into the autophagosomal and lysosomal compartments within the urothelium. Iron overload in urothelial cells induces ferritinophagy in an NCOA4-dependent manner causing increased iron availability for UPEC, triggering bacterial overproliferation and host cell death. Addition of even moderate levels of iron is sufficient to increase and prolong bacterial burden. Furthermore, we show that lysosomal damage due to iron overload is the specific mechanism causing host cell death. Significantly, we demonstrate that host cell death and bacterial burden can be reversed by inhibition of autophagy or inhibition of iron-regulatory proteins, or chelation of iron. Together, our findings suggest that UPEC persist in host cells by taking advantage of ferritinophagy. Thus, modulation of iron levels in the bladder may provide a therapeutic avenue to controlling UPEC persistence, epithelial cell death, and recurrent UTIs.

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Section: Discussionsupporting

confidence: 50%

Ferritinophagy drives uropathogenicEscherichia colipersistence in bladder epithelial cells

Bauckman

Mysorekar

2016

Autophagy

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“…Furthermore, during infection phagocytes and epithelial cells express other zinc-chelating proteins, such as calprotectin 41 – 43 . In the case of UPEC, which invades the urinary tract, it inevitably faces zinc-limiting conditions since zinc concentration in human urine was reported to range between 0.17 and 0.5 ppm (2.6 to 7.6 µM) in healthy subjects, being one of the human corporal fluids with lowest zinc concentration reported 39 , 44 , 45 . Furthermore, UPEC probably encounters zinc starvation during intracellular growth, where bioavailable zinc is limited due to sequestration by host proteins like metallothioneins.…”

Section: Discussionmentioning

confidence: 99%

A new role for Zinc limitation in bacterial pathogenicity: modulation of α-hemolysin from uropathogenic Escherichia coli

Velasco

Wang

Sanet

et al. 2018

Sci Rep

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Metal limitation is a common situation during infection and can have profound effects on the pathogen’s success. In this report, we examine the role of zinc limitation in the expression of a virulence factor in uropathogenic Escherichia coli. The pyelonephritis isolate J96 carries two hlyCABD operons that encode the RTX toxin α-hemolysin. While the coding regions of both operons are largely conserved, the upstream sequences, including the promoters, are unrelated. We show here that the two hlyCABD operons are differently regulated. The hlyII operon is efficiently silenced in the presence of zinc and highly expressed when zinc is limited. In contrast, the hlyI operon does not respond to zinc limitation. Genetic studies reveal that zinc-responsive regulation of the hlyII operon is controlled by the Zur metalloregulatory protein. A Zur binding site was identified in the promoter sequence of the hlyII operon, and we observe direct binding of Zur to this promoter region. Moreover, we find that Zur regulation of the hlyII operon modulates the ability of E. coli J96 to induce a cytotoxic response in host cell lines in culture. Our report constitutes the first description of the involvement of the zinc-sensing protein Zur in directly modulating the expression of a virulence factor in bacteria.

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“…En relación con la proteína TcpC recientemente descrita como interferente en la producción de citoquinas proinflamatorias en la ITU (12) , no fue encontrada en ninguna de las UPEC evaluadas, lo cual puede reflejar la ausencia de la isla de patogenicidad tipo IV, dependiente de su transferencia horizontal, o la reciente adquisición evolutiva del gen en las E. coli extraintestinales (12) . En relación con la respuesta inmunológica y bioquímica observada en los adultos mayores, el hierro, escaso en el fluido urinario, es indispensable en el metabolismo bacteriano (13,14) , los microorganismos que infectan el tracto urinario deben tener la capacidad de captar y competir por su asimilación (14) . Las UPEC tienen tres sistemas de captación de hierro (sideróforos, hemóforos y captación directa de hierro en su estado ferroso) y se ha informado el aumento de su expresión in vivo (15) .…”

Section: Discussionunclassified

Respuesta inmunológica y bioquímica de ancianos con infección urinaria frente factores de virulencia en Escherichia coli uropatógenas

Gonzales-Rodríguez

Varillas

Pastor

et al. 2020

Rev Peru Med Exp Salud Publica

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Con el objetivo de evidenciar diferencias en la respuesta inmunológica y bioquímica de ancianos con infección del tracto urinario (ITU) por Escherichia coli (E. coli) frente a factores de virulencia de importancia en la patogenia de la ITU, se realizó un estudio descriptivo en el cual se evaluaron 24 muestras de orina de adultos mayores con ITU provenientes de centros de reposo gerontológicos. Se determinó la concentración de hierro, TNF-α, IL-1β y la capacidad antioxidante en la orina, encontrándose una relación entre una mayor concentración de hierro y de hematíes en la orina con la presencia del gen pap GII en la E. coli. Se concluye que los adultos mayores con ITU por E. coli portadoras del gen pap GII, presentan mayor daño tisular.

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Impact of Aging on Urinary Excretion of Iron and Zinc

Cited by 12 publications

References 17 publications

Ferritinophagy drives uropathogenicEscherichia colipersistence in bladder epithelial cells

Ferritinophagy drives uropathogenicEscherichia colipersistence in bladder epithelial cells

A new role for Zinc limitation in bacterial pathogenicity: modulation of α-hemolysin from uropathogenic Escherichia coli

Respuesta inmunológica y bioquímica de ancianos con infección urinaria frente factores de virulencia en Escherichia coli uropatógenas

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