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

2011 ◽  
Vol 79 (8) ◽  
pp. 3309-3316 ◽  
Author(s):  
Michael A. Bachman ◽  
Jennifer E. Oyler ◽  
Samuel H. Burns ◽  
Mélissa Caza ◽  
François Lépine ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Respiratory Tract ◽  
Ex Vivo ◽  
Iron Acquisition ◽  
Opportunistic Pathogen ◽  
Respiratory Pathogen ◽  
Lipocalin 2 ◽  
Content Type ◽  
Tract Infections ◽  
Disseminated Disease

ABSTRACTKlebsiella pneumoniaeis a pathogen of increasing concern because of multidrug resistance, especially due toK. pneumoniaecarbapenemases (KPCs).K. pneumoniaemust acquire iron to replicate, and it utilizes iron-scavenging siderophores, such as enterobactin (Ent). The innate immune protein lipocalin 2 (Lcn2) is able to specifically bind Ent and disrupt iron acquisition. To determine whetherK. pneumoniaemust produce Lcn2-resistant siderophores to cause disease, we examined siderophore production by clinical isolates (n= 129) from respiratory, urine, blood, and stool samples and by defined siderophore mutants through genotyping and liquid chromatography-mass spectrometry. Three categories ofK. pneumoniaeisolates were identified: enterobactin positive (Ent+) (81%), enterobactin and yersiniabactin positive (Ent+Ybt+) (17%), and enterobactin and salmochelin (glycosylated Ent) positive (Ent+gly-Ent+) with or without Ybt (2%). Ent+Ybt+strains were significantly overrepresented among respiratory tract isolates (P= 0.0068) and β-lactam-resistant isolates (P= 0.0019), including the epidemic KPC-producing clone multilocus sequence type 258 (ST258). Inex vivogrowth assays, gly-Ent but not Ybt allowed evasion of Lcn2 in human serum, whereas siderophores were dispensable for growth in human urine. In a murine pneumonia model, an Ent+strain was an opportunistic pathogen that was completely inhibited by Lcn2 but caused severe, disseminated disease inLcn2−/−mice. In contrast, an Ent+Ybt+strain was a frank respiratory pathogen, causing pneumonia despite Lcn2. However, Lcn2 retained partial protection against disseminated disease. In summary, Ybt is a virulence factor that is prevalent among KPC-producingK. pneumoniaeisolates and promotes respiratory tract infections through evasion of Lcn2.

scholarly journals Complete Genome Sequence of Pseudomonas aeruginosa Strain AA2 (LMG 27630), an Early Isolate Recovered from the Airway of a German Cystic Fibrosis Patient

2020 ◽  
Vol 9 (26) ◽  
Author(s):  
Andrea Sass ◽  
Tom Coenye
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Respiratory Tract ◽  
Cystic Fibrosis Patient ◽  
Genome Sequence ◽  
Complete Genome Sequence ◽  
Opportunistic Pathogen ◽  
Content Type ◽  
Airway Infections ◽  
Early Isolate

ABSTRACT Pseudomonas aeruginosa is an opportunistic pathogen that is able to cause various infections, including airway infections in cystic fibrosis patients. Here, we present the complete closed and annotated genome sequence of P. aeruginosa AA2, an isolate obtained early during infection of the respiratory tract of a German cystic fibrosis patient.

scholarly journals Role of Human Bocavirus Respiratory Tract Infection in Hematopoietic Cell Transplant Recipients

2020 ◽  
Author(s):  
Chikara Ogimi ◽  
Emily T Martin ◽  
Hu Xie ◽  
Angela P Campbell ◽  
Alpana Waghmare ◽  
...  
Keyword(s):  
Respiratory Tract ◽  
Lower Respiratory Tract ◽  
Hematopoietic Cell ◽  
Respiratory Pathogen ◽  
Human Bocavirus ◽  
Cell Transplant ◽  
Transplant Recipients ◽  
Hematopoietic Cell Transplant ◽  
Tract Infections ◽  
The Impact

Abstract Background Limited data exist regarding the impact of human bocavirus (BoV) in hematopoietic cell transplant (HCT) recipients. Methods In a longitudinal surveillance study among allogeneic HCT recipients, pre-HCT and weekly post-HCT nasal washes and symptom surveys were collected through day 100, then at least every 3 months through 1 year post-HCT at the Fred Hutchinson Cancer Research Center (2005–2010). Samples were tested by multiplex semiquantitative polymerase chain reaction (PCR) for 12 viruses. Plasma samples from BoV + subjects were analyzed by PCR. Separately, we conducted a retrospective review of HCT recipients with BoV detected in lower respiratory tract specimens. Results Among 51 children and 420 adults in the prospective cohort, 21 distinct BoV respiratory tract infections (RTIs) were observed by 1 year post-HCT in 19 patients. Younger age and exposure to children were risk factors for BoV acquisition. Univariable models among patients with BoV RTI showed higher peak viral load in nasal samples (P = .04) and presence of respiratory copathogens (P = .03) were associated with presence of respiratory symptoms, but BoV plasma detection was not. Only watery eyes and rhinorrhea were associated with BoV RTI in adjusted models. With additional chart review, we identified 6 HCT recipients with BoV detected in lower respiratory tract specimens (incidence rate of 0.4% [9/2509] per sample tested). Although all cases presented with hypoxemia, 4 had respiratory copathogens or concomitant conditions that contributed to respiratory compromise. Conclusions BoV RTI is infrequent in transplant recipients and associated with mild symptoms. Our studies did not demonstrate convincing evidence that BoV is a serious respiratory pathogen.

scholarly journals Comparative Effectiveness of Aminoglycosides, Polymyxin B, and Tigecycline for Clearance of Carbapenem-Resistant Klebsiella pneumoniae from Urine

2011 ◽  
Vol 55 (12) ◽  
pp. 5893-5899 ◽  
Author(s):  
Michael J. Satlin ◽  
Christine J. Kubin ◽  
Jill S. Blumenthal ◽  
Andrew B. Cohen ◽  
E. Yoko Furuya ◽  
...  
Keyword(s):  
New York ◽  
Klebsiella Pneumoniae ◽  
Urine Culture ◽  
Active Agent ◽  
Polymyxin B ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Tract Infections

ABSTRACTCarbapenem-resistantKlebsiella pneumoniae(CRKP) is an increasingly common cause of health care-associated urinary tract infections. Antimicrobials within vitroactivity against CRKP are typically limited to polymyxins, tigecycline, and often, aminoglycosides. We conducted a retrospective cohort study of cases of CRKP bacteriuria at New York-Presbyterian Hospital from January 2005 through June 2010 to compare microbiologic clearance rates based on the use of polymyxin B, tigecycline, or an aminoglycoside. We constructed three active antimicrobial cohorts based on the active agent used and an untreated cohort of cases that did not receive antimicrobial therapy with Gram-negative activity. Microbiologic clearance was defined as having a follow-up urine culture that did not yield CRKP. Cases without an appropriate follow-up culture or that received multiple active agents or less than 3 days of the active agent were excluded. Eighty-seven cases were included in the active antimicrobial cohorts, and 69 were included in the untreated cohort. The microbiologic clearance rate was 88% in the aminoglycoside cohort (n= 41), compared to 64% in the polymyxin B (P= 0.02;n= 25), 43% in the tigecycline (P< 0.001;n= 21), and 36% in the untreated (P< 0.001;n= 69) cohorts. Using multivariate analysis, the odds of clearance were lower for the polymyxin B (odds ratio [OR], 0.10;P= 0.003), tigecycline (OR, 0.08;P= 0.001), and untreated (OR, 0.14;P= 0.003) cohorts than for the aminoglycoside cohort. Treatment with an aminoglycoside, when activein vitro, was associated with a significantly higher rate of microbiologic clearance of CRKP bacteriuria than treatment with either polymyxin B or tigecycline.

scholarly journals Dopamine Is a Siderophore-Like Iron Chelator That PromotesSalmonella entericaSerovar Typhimurium Virulence in Mice

mBio ◽  
2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Stefanie Dichtl ◽  
Egon Demetz ◽  
David Haschka ◽  
Piotr Tymoszuk ◽  
Verena Petzer ◽  
...  
Keyword(s):  
Bacterial Growth ◽  
Iron Uptake ◽  
Iron Homeostasis ◽  
Iron Acquisition ◽  
Lipocalin 2 ◽  
Intracellular Iron ◽  
Content Type ◽  
Hepcidin Expression

ABSTRACTWe have recently shown that the catecholamine dopamine regulates cellular iron homeostasis in macrophages. As iron is an essential nutrient for microbes, and intracellular iron availability affects the growth of intracellular bacteria, we studied whether dopamine administration impacts the course ofSalmonellainfections. Dopamine was found to promote the growth ofSalmonellaboth in culture and within bone marrow-derived macrophages, which was dependent on increased bacterial iron acquisition. Dopamine administration to mice infected withSalmonella entericaserovar Typhimurium resulted in significantly increased bacterial burdens in liver and spleen, as well as reduced survival. The promotion of bacterial growth by dopamine was independent of the siderophore-binding host peptide lipocalin-2. Rather, dopamine enhancement of iron uptake requires both the histidine sensor kinase QseC and bacterial iron transporters, in particular SitABCD, and may also involve the increased expression of bacterial iron uptake genes. Deletion or pharmacological blockade of QseC reduced but did not abolish the growth-promoting effects of dopamine. Dopamine also modulated systemic iron homeostasis by increasing hepcidin expression and depleting macrophages of the iron exporter ferroportin, which enhanced intracellular bacterial growth.Salmonellalacking all central iron uptake pathways failed to benefit from dopamine treatment. These observations are potentially relevant to critically ill patients, in whom the pharmacological administration of catecholamines to improve circulatory performance may exacerbate the course of infection with siderophilic bacteria.IMPORTANCEHere we show that dopamine increases bacterial iron incorporation and promotesSalmonellaTyphimurium growth bothin vitroandin vivo. These observations suggest the potential hazards of pharmacological catecholamine administration in patients with bacterial sepsis but also suggest that the inhibition of bacterial iron acquisition might provide a useful approach to antimicrobial therapy.

scholarly journals Identification of Pneumococcal Factors Affecting Pneumococcal Shedding Shows that thedltLocus Promotes Inflammation and Transmission

mBio ◽  
2019 ◽  
Vol 10 (3) ◽  
Author(s):  
M. Ammar Zafar ◽  
Alexandria J. Hammond ◽  
Shigeto Hamaguchi ◽  
Weisheng Wu ◽  
Masamitsu Kono ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Respiratory Tract ◽  
Capsular Polysaccharide ◽  
Inflammatory Responses ◽  
Transposon Mutagenesis ◽  
Respiratory Pathogen ◽  
Invasive Infection ◽  
Upper Respiratory Tract ◽  
Content Type ◽  
Upper Respiratory

ABSTRACTHost-to-host transmission is a necessary but poorly understood aspect of microbial pathogenesis. Herein, we screened a genomic library of mutants of the leading respiratory pathogenStreptococcus pneumoniaegenerated by mariner transposon mutagenesis (Tn-Seq) to identify genes contributing to its exit or shedding from the upper respiratory tract (URT), the limiting step in the organism’s transmission in an infant mouse model. Our analysis focused on genes affecting the bacterial surface that directly impact interactions with the host. Among the multiple factors identified was thedltlocus, which addsd-alanine onto lipoteichoic acids (LTA) and thereby increases Toll-like receptor 2-mediated inflammation and resistance to antimicrobial peptides. The more robust proinflammatory response in the presence ofd-alanylation promotes secretions that facilitate pneumococcal shedding and allows for transmission. Expression of thedltlocus is controlled by the CiaRH system, which senses cell wall stress in response to antimicrobial activity, including in response to lysozyme, the most abundant antimicrobial along the URT mucosa. Accordingly, in alysM−/−host, there was no longer an effect of thedltlocus on pneumococcal shedding. Thus, our findings demonstrate how a pathogen senses the URT milieu and then modifies its surface characteristics to take advantage of the host response for transit to another host.IMPORTANCEStreptococcus pneumoniae(the pneumococcus) is a common cause of respiratory tract and invasive infection. The overall effectiveness of immunization with the organism’s capsular polysaccharide depends on its ability to block colonization of the upper respiratory tract and thereby prevent host-to-host transmission. Because of the limited coverage of current pneumococcal vaccines, we carried out an unbiasedin vivotransposon mutagenesis screen to identify pneumococcal factors other than its capsular polysaccharide that affect transmission. One such candidate was expressed by thedltlocus, previously shown to addd-alanine onto the pneumococcal lipoteichoic acid present on the bacterial cell surface. This modification protects against host antimicrobials and augments host inflammatory responses. The latter increases secretions and bacterial shedding from the upper respiratory tract to allow for transmission. Thus, this study provides insight into a mechanism employed by the pneumococcus to successfully transit from one host to another.

scholarly journals Klebsiella pneumoniae Expressing VIM-1 Metallo-β-Lactamase Is Resensitized to Cefotaxime via Thiol-Mediated Zinc Chelation

2019 ◽  
Vol 88 (1) ◽  
Author(s):  
Harpa Karadottir ◽  
Maarten Coorens ◽  
Zhihai Liu ◽  
Yang Wang ◽  
Birgitta Agerberth ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Ex Vivo ◽  
Reductase Activity ◽  
Urine Samples ◽  
Dependent Manner ◽  
Content Type ◽  
Endogenous Factors ◽  
Reducing Ability ◽  
Zinc Chelation ◽  
Ht 29

ABSTRACT Antibiotic-resistant Klebsiella pneumoniae isolates constitute a great clinical challenge. One important resistance mechanism in K. pneumoniae is the metallo-β-lactamases (MBLs), which require zinc for their function. Thus, zinc chelation could be a strategy to resensitize K. pneumoniae to β-lactams. However, the potential role for endogenous zinc chelators for this purpose remains to be explored. The aim was to search for endogenous factors that could resensitize MBL-expressing K. pneumoniae to cefotaxime (CTX). Clinical K. pneumoniae isolates expressing different MBLs were screened for sensitivity to CTX in supernatants from human HT-29 colonic epithelial cells. Factors influencing CTX susceptibility were isolated and identified with chromatographic and biochemical methods. Free zinc was measured with a Zinquin assay, the thiol content was assessed with a fluorometric thiol assay, and the reducing ability of the supernatant was measured with a fluorescent l-cystine probe. Urine samples from healthy volunteers were used to validate findings ex vivo. VIM-1-expressing K. pneumoniae regained susceptibility to CTX when grown in supernatants from HT-29 cells. This effect was mediated via free thiols in the supernatant, including l-cysteine, and could be prevented by inhibiting thioredoxin reductase activity in the supernatant. Free thiols in urine samples appeared to have a similar function in restoring CTX activity against VIM-1-expressing K. pneumoniae in a zinc-dependent manner. We have identified l-cysteine as an endogenous zinc chelator resulting in the resensitization of VIM-1-expressing K. pneumoniae to CTX. These results suggest that natural zinc chelators in combination with conventional antibiotics could be used to treat infections caused by VIM-1-expressing pathogens.

scholarly journals Dectin-1-Dependent Interleukin-22 Contributes to Early Innate Lung Defense against Aspergillus fumigatus

2011 ◽  
Vol 80 (1) ◽  
pp. 410-417 ◽  
Author(s):  
Melissa A. Gessner ◽  
Jessica L. Werner ◽  
Lauren M. Lilly ◽  
Michael P. Nelson ◽  
Allison E. Metz ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Ex Vivo ◽  
Lung Cells ◽  
Lipocalin 2 ◽  
Beta Glucan ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Deficient Mice ◽  
Lung Defense

ABSTRACTWe have previously reported that mice deficient in the beta-glucan receptor Dectin-1 displayed increased susceptibility toAspergillus fumigatuslung infection in the presence of lower interleukin 23 (IL-23) and IL-17A production in the lungs and have reported a role for IL-17A in lung defense. As IL-23 is also thought to control the production of IL-22, we examined the role of Dectin-1 in IL-22 production, as well as the role of IL-22 in innate host defense againstA. fumigatus. Here, we show that Dectin-1-deficient mice demonstrated significantly reduced levels of IL-22 in the lungs early afterA. fumigatuschallenge. Culturing cells from enzymatic lung digestsex vivofurther demonstrated Dectin-1-dependent IL-22 production. IL-22 production was additionally found to be independent of IL-1β, IL-6, or IL-18 but required IL-23. The addition of recombinant IL-23 augmented IL-22 production in wild-type (WT) lung cells and rescued IL-22 production by lung cells from Dectin-1-deficient mice.In vivoneutralization of IL-22 in the lungs of WT mice resulted in impairedA. fumigatuslung clearance. Moreover, mice deficient in IL-22 also demonstrated a higher lung fungal burden afterA. fumigatuschallenge in the presence of impaired IL-1α, tumor necrosis factor alpha (TNF-α), CCL3/MIP-1α, and CCL4/MIP-1β production and lower neutrophil recruitment, yet intact IL-17A production. We further show that lung lavage fluid collected from bothA. fumigatus-challenged Dectin-1-deficient and IL-22-deficient mice had compromised anti-fungal activity againstA. fumigatus in vitro. Although lipocalin 2 production was observed to be Dectin-1 and IL-22 dependent, lipocalin 2-deficient mice did not demonstrate impairedA. fumigatusclearance. Moreover, lungS100a8,S100a9, andReg3gmRNA expression was not lower in either Dectin-1-deficient or IL-22-deficient mice. Collectively, our results indicate that early innate lung defense againstA. fumigatusis mediated by Dectin-1-dependent IL-22 production.

scholarly journals Klebsiella pneumoniae: Going on the Offense with a Strong Defense

2016 ◽  
Vol 80 (3) ◽  
pp. 629-661 ◽  
Author(s):  
Michelle K. Paczosa ◽  
Joan Mecsas
Keyword(s):  
Klebsiella Pneumoniae ◽  
Critical Role ◽  
Infection Model ◽  
Interleukin 17 ◽  
Regulation Of Transcription ◽  
Antibiotic Resistant ◽  
Content Type ◽  
Recent Emergence ◽  
Wide Range ◽  
Tract Infections

SUMMARYKlebsiella pneumoniaecauses a wide range of infections, including pneumonias, urinary tract infections, bacteremias, and liver abscesses. Historically,K. pneumoniaehas caused serious infection primarily in immunocompromised individuals, but the recent emergence and spread of hypervirulent strains have broadened the number of people susceptible to infections to include those who are healthy and immunosufficient. Furthermore,K. pneumoniaestrains have become increasingly resistant to antibiotics, rendering infection by these strains very challenging to treat. The emergence of hypervirulent and antibiotic-resistant strains has driven a number of recent studies. Work has described the worldwide spread of one drug-resistant strain and a host defense axis, interleukin-17 (IL-17), that is important for controlling infection. Four factors, capsule, lipopolysaccharide, fimbriae, and siderophores, have been well studied and are important for virulence in at least one infection model. Several other factors have been less well characterized but are also important in at least one infection model. However, there is a significant amount of heterogeneity inK. pneumoniaestrains, and not every factor plays the same critical role in all virulentKlebsiellastrains. Recent studies have identified additionalK. pneumoniaevirulence factors and led to more insights about factors important for the growth of this pathogen at a variety of tissue sites. Many of these genes encode proteins that function in metabolism and the regulation of transcription. However, much work is left to be done in characterizing these newly discovered factors, understanding how infections differ between healthy and immunocompromised patients, and identifying attractive bacterial or host targets for treating these infections.

scholarly journals Role of Acinetobactin-Mediated Iron Acquisition Functions in the Interaction of Acinetobacter baumannii Strain ATCC 19606Twith Human Lung Epithelial Cells, Galleria mellonella Caterpillars, and Mice

2012 ◽  
Vol 80 (3) ◽  
pp. 1015-1024 ◽  
Author(s):  
Jennifer A. Gaddy ◽  
Brock A. Arivett ◽  
Michael J. McConnell ◽  
Rafael López-Rojas ◽  
Jerónimo Pachón ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Acinetobacter Baumannii ◽  
Galleria Mellonella ◽  
Ex Vivo ◽  
Iron Acquisition ◽  
Alveolar Epithelial Cells ◽  
Lung Epithelial Cells ◽  
Content Type ◽  
Alveolar Epithelial

Acinetobacter baumannii, which causes serious infections in immunocompromised patients, expresses high-affinity iron acquisition functions needed for growth under iron-limiting laboratory conditions. In this study, we determined that the initial interaction of the ATCC 19606Ttype strain with A549 human alveolar epithelial cells is independent of the production of BasD and BauA, proteins needed for acinetobactin biosynthesis and transport, respectively. In contrast, these proteins are required for this strain to persist within epithelial cells and cause their apoptotic death. Infection assays usingGalleria mellonellalarvae showed that impairment of acinetobactin biosynthesis and transport functions significantly reduces the ability of ATCC 19606Tcells to persist and kill this host, a defect that was corrected by adding inorganic iron to the inocula. The results obtained with theseex vivoandin vivoapproaches were validated using a mouse sepsis model, which showed that expression of the acinetobactin-mediated iron acquisition system is critical for ATCC 19606Tto establish an infection and kill this vertebrate host. These observations demonstrate that the virulence of the ATCC 19606Tstrain depends on the expression of a fully active acinetobactin-mediated system. Interestingly, the three models also showed that impairment of BasD production results in an intermediate virulence phenotype compared to those of the parental strain and the BauA mutant. This observation suggests that acinetobactin intermediates or precursors play a virulence role, although their contribution to iron acquisition is less relevant than that of mature acinetobactin.

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