Intracellular Uropathogenic E. coli Exploits Host Rab35 for Iron Acquisition and Survival within Urinary Bladder Cells

Dikshit, Neha; Bist, Pradeep; Fenlon, Shannon N.; Pulloor, Niyas Kudukkil; Chua, Christelle En Lin; Scidmore, Marci A.; Carlyon, Jason A.; Tang, Bor Luen; Chen, Swaine L.; Sukumaran, Bindu

doi:10.1371/journal.ppat.1005083

Cited by 50 publications

(56 citation statements)

References 83 publications

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“…21,22 Other studies have also linked high intralysosomal iron accumulation with oxidative stress and resulting cytotoxicity 34 consistent with a recent study showing that lysosomal integrity is necessary for UPEC to take advantage of excess bioavailable iron. 59 Normal serum iron levels in healthy adults are typically under 31 mM 60 and patients with severe hemochromatosis or liver damage can exhibit levels far greater than 31. Patients with iron dysfunction are more likely to experience severe bacterial burden which may result in damage to the bladder urothelium.…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

Ferritinophagy drives uropathogenicEscherichia colipersistence in bladder epithelial cells

Bauckman

Mysorekar

2016

Autophagy

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“…Our work has revealed a novel mechanism of iron limitation during UTI where ceruloplasmin catalyzes the production of Fe 3ϩ ions that are then loaded onto transferrin in urine. During UPEC colonization, urothelial cells upregulate the expression of transferrin receptors that then rapidly import holotransferrin to deplete iron from the extracellular milieu (45). Therefore, we posit that Cu mobilization to urine exerts distinct yet convergent effects to limit bacterial survival by direct bactericidal action, by bactericidal action via delivery of Cu, and also indirectly by inducing iron starvation (Fig.…”

Section: Fig 12mentioning

confidence: 99%

Copper Is a Host Effector Mobilized to Urine during Urinary Tract Infection To Impair Bacterial Colonization

et al. 2017

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Urinary tract infection (UTI) is a major global infectious disease affecting millions of people annually. Human urinary copper (Cu) content is elevated during UTI caused by uropathogenic Escherichia coli (UPEC). UPEC upregulates the expression of Cu efflux genes during clinical UTI in patients as an adaptive response to host-derived Cu. Whether Cu is mobilized to urine as a host response to UTI and its role in protection against UTI remain unresolved. To address these questions, we tested the hypothesis that Cu is a host effector mobilized to urine during UTI to limit bacterial growth. Our results reveal that Cu is mobilized to urine during UTI caused by the major uropathogens Proteus mirabilis and Klebsiella pneumoniae, in addition to UPEC, in humans. Ceruloplasmin, a Cu-containing ferroxidase, is found at higher levels in UTI urine than in healthy control urine and serves as the molecular source of urinary Cu during UTI. Our results demonstrate that ceruloplasmin decreases the bioavailability of iron in urine by a transferrin-dependent mechanism. Experimental UTI with UPEC in nonhuman primates recapitulates the increased urinary Cu content observed during clinical UTI. Furthermore, Cu-deficient mice are highly colonized by UPEC, indicating that Cu is involved in the limiting of bacterial growth within the urinary tract. Collectively, our results indicate that Cu is a host effector that is involved in protection against pathogen colonization of the urinary tract. Because urinary Cu levels are amenable to modulation, augmentation of the Cu-based host defense against UTI represents a novel approach to limiting bacterial colonization during UTI. KEYWORDS UTI, urinary tract infection, uropathogenic E. coli, UPEC, copper, ceruloplasmin U rinary tract infection (UTI) is an extremely common infectious disease in the UnitedStates and around the world (1, 2). In the United States alone, UTI leads to 11 million physician visits, 1.7 million emergency room visits, and 470,000 hospitalizations annually, with a direct cost of $3.5 billion (2). Infection of the urinary bladder (cystitis) is the most common form of UTI, whereas kidney infection (pyelonephritis), bacteremia, and sepsis are less common but more serious outcomes of UTI (3, 4). Women are four times as likely to develop UTI as men are because of anatomic differences (4). Children, the elderly, and individuals with catheters, anatomic and physiologic abnormalities of the urinary tract, uroliths, or diabetes mellitus are also highly susceptible to UTI (4).Uropathogenic Escherichia coli (UPEC) is the etiological agent in ϳ85% of the cystitis cases in otherwise healthy people (3). Free-living, adherent, biofilm, and intracellular forms of UPEC are found in the urinary bladder (5, 6). UPEC utilizes multiple virulence factors, including type 1 fimbriae, P fimbriae, flagella, toxins, and iron acquisition systems, to cause UTI (2, 7). In addition to UPEC, Klebsiella pneumoniae and Proteus

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“…The superficial umbrella cells of the bladder are the initial targets of host cell invasion by UPEC, but the exfoliation of these cells and the influx of neutrophils during the course of a UTI can provide UPEC with access to deeper layers of immature host cells within the urothelium (83,88,89). Within both mature and immature bladder epithelial cells, internalized bacteria that are not immediately expelled are trafficked into membrane-bound compartments that have characteristics of late endosomes and early lysosomes (84,85,90). Specifically, these UPEC-containing vacuoles incorporate the host proteins CD63 and LAMP-1 and the lipid lysobisphosphatidic acid (LBPA) but lack the protease cathepsin-D.…”

Section: The Life Cycle Of Upecmentioning

confidence: 99%

“…Recently, culture systems that incorporate different types of host cells, such as neutrophils plus bladder epithelial cells, have been established to better approximate the cellular complexity of the inflamed urothelium (156). By using small interfering RNA (siRNA) as well as plasmid and viral constructs, host genes within cultured cells can be specifically silenced or, alternatively, overexpressed, facilitating the functional analysis of host factors that may contribute to the pathogenesis of UTIs (58,90,(157)(158)(159). Pharmacological reagents can also be used to interfere with host enzymes and signaling cascades, but consideration should always be given to dosage and off-target effects as well as potential interference with bacterial processes.…”

Section: Cell Culturementioning

confidence: 99%

“…The use of cultured eukaryotic cells has been instrumental in the identification of host receptors that are bound by UPEC as well as the delineation of downstream signaling events that modulate inflammation and the internalization and trafficking of bacteria (58,72,77,90,129,(157)(158)(159)(162)(163)(164)(165)(166)(167)(168)(169)(170)(171). Cell culture-based assays are also commonly used to define how secreted toxins and other UPEC-associated virulence factors affect host cell functions and viability (172)(173)(174)(175)(176)(177)(178)(179)(180).…”

Section: Cell Culturementioning

confidence: 99%

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Strengths and Limitations of Model Systems for the Study of Urinary Tract Infections and Related Pathologies

Barber

Norton

Wiles

et al. 2016

Microbiol Mol Biol Rev

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SUMMARYUrinary tract infections (UTIs) are some of the most common bacterial infections worldwide and are a source of substantial morbidity among otherwise healthy women. UTIs can be caused by a variety of microbes, but the predominant etiologic agent of these infections is uropathogenicEscherichia coli(UPEC). An especially troubling feature of UPEC-associated UTIs is their high rate of recurrence. This problem is compounded by the drastic increase in the global incidence of antibiotic-resistant UPEC strains over the past 15 years. The need for more-effective treatments for UTIs is driving research aimed at bettering our understanding of the virulence mechanisms and host-pathogen interactions that occur during the course of these infections. Surrogate models of human infection, including cell culture systems and the use of murine, porcine, avian, teleost (zebrafish), and nematode hosts, are being employed to define host and bacterial factors that modulate the pathogenesis of UTIs. These model systems are revealing how UPEC strains can avoid or overcome host defenses and acquire scarce nutrients while also providing insight into the virulence mechanisms used by UPEC within compromised individuals, such as catheterized patients. Here, we summarize our current understanding of UTI pathogenesis while also giving an overview of the model systems used to study the initiation, persistence, and recurrence of UTIs and life-threatening sequelae like urosepsis. Although we focus on UPEC, the experimental systems described here can also provide valuable insight into the disease processes associated with other bacterial pathogens both within the urinary tract and elsewhere within the host.

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Intracellular Uropathogenic E. coli Exploits Host Rab35 for Iron Acquisition and Survival within Urinary Bladder Cells

Cited by 50 publications

References 83 publications

Ferritinophagy drives uropathogenicEscherichia colipersistence in bladder epithelial cells

Ferritinophagy drives uropathogenicEscherichia colipersistence in bladder epithelial cells

Copper Is a Host Effector Mobilized to Urine during Urinary Tract Infection To Impair Bacterial Colonization

Strengths and Limitations of Model Systems for the Study of Urinary Tract Infections and Related Pathologies

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