Klebsiella pneumoniae Yersiniabactin Promotes Respiratory Tract Infection through Evasion of Lipocalin 2

Bachman, Michael A.; Oyler, Jennifer E.; Burns, Samuel H.; Caza, Mélissa; Lépine, François; Dozois, Charles M.; Weiser, Jeffrey N.

doi:10.1128/iai.05114-11

Cited by 254 publications

(298 citation statements)

References 36 publications

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“…Studies have shown that disrupting siderophore biosynthesis impacts central metabolism, which could affect the elaboration of other virulence factors and ultimately pathogenesis (48). Alternatively, elevated Ent levels have been detected in bacterial strains with mutations in the Aer and Ybt pathways, which could improve pathogenesis (49,50). Elevated Ent levels in ybtS-iucA may also explain the surprising increase in kidney colonization of cBSA-vaccinated mice infected with ybtS-iucA compared with iucA ( Fig.…”

Section: Resultsmentioning

confidence: 95%

Siderophore vaccine conjugates protect against uropathogenicEscherichia coliurinary tract infection

Mike

Smith

Sumner

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Uropathogenic Escherichia coli (UPEC) is the primary cause of uncomplicated urinary tract infections (UTIs). Whereas most infections are isolated cases, 1 in 40 women experience recurrent UTIs. The rise in antibiotic resistance has complicated the management of chronic UTIs and necessitates new preventative strategies. Currently, no UTI vaccines are approved for use in the United States, and the development of a highly effective vaccine remains elusive. Here, we have pursued a strategy for eliciting protective immunity by vaccinating with small molecules required for pathogenesis, rather than proteins or peptides. Small iron-chelating molecules called siderophores were selected as antigens to vaccinate against UTI for this vaccine strategy. These pathogen-associated stealth siderophores evade host immune defenses and enhance bacterial virulence. Previous animal studies revealed that vaccination with siderophore receptor proteins protects against UTI. The poor solubility of these integral outer-membrane proteins in aqueous solutions limits their practical utility. Because their cognate siderophores are water soluble, we hypothesized that these bacterial-derived small molecules are prime vaccine candidates. To test this hypothesis, we immunized mice with siderophores conjugated to an immunogenic carrier protein. The siderophore-protein conjugates elicited an adaptive immune response that targeted bacterial stealth siderophores and protected against UTI. Our study has identified additional antigens suitable for a multicomponent UTI vaccine and highlights the potential use of bacterial-derived small molecules as antigens in vaccine therapies.vaccine conjugate | urinary tract infection | siderophore | UPEC | iron acquisition

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Section: Resultsmentioning

confidence: 95%

Siderophore vaccine conjugates protect against uropathogenicEscherichia coliurinary tract infection

Mike

Smith

Sumner

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…The presence of pulmonary LCN2 per se could concurrently explain the dominance of LCN2-resistant bacteria such as S. pneumoniae or Haemophilus influenzae as causative pathogens of pneumonia. Klebsiella pneumoniae, another relevant lung pathogen that depends on enterobactin-like siderophores, evolved LCN2-resistant strains to evade LCN2-mediated growth inhibition (44).…”

Section: Discussionmentioning

confidence: 99%

Lipocalin 2 deactivates macrophages and worsens pneumococcal pneumonia outcomes

Warszawska¹,

Gawish²,

Sharif³

et al. 2013

J. Clin. Invest.

126

123

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Macrophages play a key role in responding to pathogens and initiate an inflammatory response to combat microbe multiplication. Deactivation of macrophages facilitates resolution of the inflammatory response. Deactivated macrophages are characterized by an immunosuppressive phenotype, but the lack of unique markers that can reliably identify these cells explains the poorly defined biological role of this macrophage subset. We identified lipocalin 2 (LCN2) as both a marker of deactivated macrophages and a macrophage deactivator. We show that LCN2 attenuated the early inflammatory response and impaired bacterial clearance, leading to impaired survival of mice suffering from pneumococcal pneumonia. LCN2 induced IL-10 formation by macrophages, skewing macrophage polarization in a STAT3-dependent manner. Pulmonary LCN2 levels were tremendously elevated during bacterial pneumonia in humans, and high LCN2 levels were indicative of a detrimental outcome from pneumonia with Gram-positive bacteria. Our data emphasize the importance of macrophage deactivation for the outcome of pneumococcal infections and highlight the role of LCN2 and IL-10 as determinants of macrophage performance in the respiratory tract.

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“…While individual iron uptake mechanisms uniquely contribute to bacterial pathogenesis (13,40), it seems reasonable to assume that their similar function would allow for compensation. Of the four siderophores that UPEC isolates produce, three are so-called "stealth" siderophores (salmochelin, yersiniabactin, aerobactin) for their ability to avoid sequestration by lipocalin-2 (40,41). Isolating UPEC strains with all three stealth siderophore systems is uncommon, possibly due to their outer membrane receptors being the frequent target of bacteriophages and bacteriocins (42).…”

Section: Figmentioning

confidence: 99%

“…In addition, yersiniabactin is disproportionately associated with antibiotic-resistant strains, including Ͼ90% of strains of the E. coli sequence type 131 (ST131), an alarming pandemic multidrug-resistant (MDR) clonal group (48)(49)(50)(51), and Ͼ60% of respiratory carbapenemase-producing K. pneumoniae strains, compared to 10% of susceptible K. pneumoniae strains (41). Novel antimicrobial agents or vaccines that target yersiniabactin iron transport or other pathogen-associated nutrient acquisition systems may provide an effective strategy to combat the rising surge of antibiotic-resistant common infections.…”

Section: Figmentioning

confidence: 99%

Blocking Yersiniabactin Import Attenuates Extraintestinal Pathogenic Escherichia coli in Cystitis and Pyelonephritis and Represents a Novel Target To Prevent Urinary Tract Infection

et al. 2015

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The emergence and spread of extended-spectrum beta-lactamases and carbapenemases among common bacterial pathogens are threatening our ability to treat routine hospital-and community-acquired infections. With the pipeline for new antibiotics virtually empty, there is an urgent need to develop novel therapeutics. Bacteria require iron to establish infection, and specialized pathogen-associated iron acquisition systems like yersiniabactin, common among pathogenic species in the family Enterobacteriaceae, including multidrug-resistant Klebsiella pneumoniae and pathogenic Escherichia coli, represent potentially novel therapeutic targets. Although the yersiniabactin system was recently identified as a vaccine target for uropathogenic E. coli (UPEC)-mediated urinary tract infection (UTI), its contribution to UPEC pathogenesis is unknown. Using an E. coli mutant (strain 536⌬fyuA) unable to acquire yersiniabactin during infection, we established the yersiniabactin receptor as a UPEC virulence factor during cystitis and pyelonephritis, a fitness factor during bacteremia, and a surface-accessible target of the experimental FyuA vaccine. In addition, we determined through transcriptome sequencing (RNA-seq) analyses of RNA from E. coli causing cystitis in women that iron acquisition systems, including the yersiniabactin system, are highly expressed by bacteria during natural uncomplicated UTI. Given that yersiniabactin contributes to the virulence of several pathogenic species in the family Enterobacteriaceae, including UPEC, and is frequently associated with multidrug-resistant strains, it represents a promising novel target to combat antibiotic-resistant infections.W idespread and increasing antibiotic resistance among bacterial pathogens that cause some of our most common health care-associated and community-acquired infections is jeopardizing our ability to prevent and treat routine infectious diseases (1). Two pathogens of particular concern are uropathogenic Escherichia coli (UPEC), which causes the majority (80%) of uncomplicated urinary tract infections (UTI) (2), and Klebsiella pneumoniae, a frequent cause of hospital-acquired pneumonia and UTI (3). Without adequate treatment, both UPEC and K. pneumoniae can breach epithelial and endothelial barriers to gain access to the bloodstream, causing life-threatening bacteremia (4). E. coli rates of resistance to fluoroquinolones and third-generation cephalosporins now exceed 50% in 5 of 6 global regions, and similar resistance rates were reported for K. pneumoniae worldwide (5). Unfortunately, the treatment of severe infections caused by these species must rely on carbapenems, the last resort to treat severe community-and hospital-acquired infections (6). Not only are these antibacterial compounds more expensive and less available in resource-constrained settings, but their extended use contributes to the spread of carbapenem-resistant Enterobacteriaceae (CRE), a serious global public health concern (7).Increasing rates of antimicrobial resistance and limited new therapeut...

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Klebsiella pneumoniae Yersiniabactin Promotes Respiratory Tract Infection through Evasion of Lipocalin 2

Cited by 254 publications

References 36 publications

Siderophore vaccine conjugates protect against uropathogenicEscherichia coliurinary tract infection

Siderophore vaccine conjugates protect against uropathogenicEscherichia coliurinary tract infection

Lipocalin 2 deactivates macrophages and worsens pneumococcal pneumonia outcomes

Blocking Yersiniabactin Import Attenuates Extraintestinal Pathogenic Escherichia coli in Cystitis and Pyelonephritis and Represents a Novel Target To Prevent Urinary Tract Infection

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