Genomic dissection of the bacterial population underlying Klebsiella pneumoniae infections in hospital patients: insights into an opportunistic pathogen

Klebsiella pneumoniae is a major cause of opportunistic healthcare-associated infections, which are increasingly complicated by the presence of extended-spectrum beta-lactamases (ESBLs) and carbapenem resistance. We conducted a year-long prospective surveillance study of K. pneumoniae clinical isolates identified in a hospital microbiological diagnostic laboratory. Disease burden was two-thirds urinary tract infections (UTI; associated with female sex and age), followed by pneumonia (15%), wound (10%) and disseminated infections/sepsis (10%). Whole-genome sequencing (WGS) revealed a diverse pathogen population, including other species within the K. pneumoniae complex (18%). Several infections were caused by K. variicola/K. pneumoniae species hybrids, one of which showed evidence of nosocomial transmission, indicating fitness to transmit and cause disease despite a lack of acquired antimicrobial resistance (AMR). A wide range of AMR phenotypes were observed and, in most cases, corresponding mechanisms were identified in the genomes, mainly in the form of plasmid-borne genes. ESBLs were correlated with presence of other acquired AMR genes (median 10). Bacterial genomic features associated with nosocomial onset of disease were ESBL genes (OR 2.34, p=0.015) and rhamnose-positive capsules (OR 3.12, p<0.001). Virulence plasmid-encoded features (aerobactin, hypermucoidy) were rare (<3%), and mostly present in community-onset cases. WGS-confirmed nosocomial transmission was rare (10% of cases) but strongly associated with ESBLs (OR 21, p<1x10-11). We estimate 28% risk of onward nosocomial transmission for ESBL-positive strains vs 1.7% for ESBL-negative strains. These data indicate the underlying burden of K. pneumoniae disease in hospitalised patients is due largely to opportunistic infections with diverse strains. However, we also identified several successful lineages that were overrepresented but not due to nosocomial transmission. These lineages were associated with ESBL, yersiniabactin, mannose+ K loci and rhamnose- K loci; most are also common in public clinical genome collections, suggesting enhanced propensity for colonisation and spread in the human population.

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Capsule Production and Glucose Metabolism Dictate Fitness duringSerratia marcescensBacteremia

mBio ◽

10.1128/mbio.00740-17 ◽

2017 ◽

Vol 8 (3) ◽

Cited By ~ 23

Author(s):

Mark T. Anderson ◽

Lindsay A. Mitchell ◽

Lili Zhao ◽

Harry L. T. Mobley

Keyword(s):

Glucose Metabolism ◽

Serratia Marcescens ◽

Opportunistic Infections ◽

Opportunistic Pathogen ◽

Extracellular Polysaccharides ◽

Mammalian Host ◽

Wild Type ◽

Transposon Insertion ◽

Capsule Production ◽

Tract Infections

ABSTRACTSerratia marcescensis an opportunistic pathogen that causes a range of human infections, including bacteremia, keratitis, wound infections, and urinary tract infections. Compared to other members of theEnterobacteriaceaefamily, the genetic factors that facilitateSerratiaproliferation within the mammalian host are less well defined. Anin vivoscreen of transposon insertion mutants identified 212S. marcescensfitness genes that contribute to bacterial survival in a murine model of bloodstream infection. Among those identified, 11 genes were located within an 18-gene cluster encoding predicted extracellular polysaccharide biosynthesis proteins. A mutation in thewzxgene contained within this locus conferred a loss of fitness in competition infections with the wild-type strain and a reduction in extracellular uronic acids correlating with capsule loss. A second gene,pgm, encoding a phosphoglucomutase exhibited similar capsule-deficient phenotypes, linking central glucose metabolism with capsule production and fitness ofSerratiaduring mammalian infection. Further evidence of the importance of central metabolism was obtained with apfkAglycolytic mutant that demonstrated reduced replication in human serum and during murine infection. An MgtB magnesium transporter homolog was also among the fitness factors identified, and anS. marcescens mgtBmutant exhibited decreased growth in defined medium containing low concentrations of magnesium and was outcompeted ~10-fold by wild-type bacteria in mice. Together, these newly identified genes provide a more complete understanding of the specific requirements forS. marcescenssurvival in the mammalian host and provide a framework for further investigation of the means by whichS. marcescenscauses opportunistic infections.IMPORTANCESerratia marcescensis a remarkably prolific organism that replicates in diverse environments, including as an opportunistic pathogen in human bacteremia. The genetic requirements forS. marcescenssurvival in the mammalian bloodstream were defined in this work by transposon insertion sequencing. In total, 212 genes that contribute to bacterial fitness were identified. When sorted via biological function, two of the major fitness categories identified herein were genes encoding capsule polysaccharide biogenesis functions and genes involved in glucose utilization. Further investigation determined that certain glucose metabolism fitness genes are also important for the generation of extracellular polysaccharides. Together, these results identify critical biological processes that allowS. marcescensto colonize the mammalian bloodstream.

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Klebsiella pneumoniae: Going on the Offense with a Strong Defense

Microbiology and Molecular Biology Reviews ◽

10.1128/mmbr.00078-15 ◽

2016 ◽

Vol 80 (3) ◽

pp. 629-661 ◽

Cited By ~ 376

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.

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Carbapenem-Resistant Klebsiella pneumoniae Urinary Tract Infection following Solid Organ Transplantation

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.04284-14 ◽

2014 ◽

Vol 59 (1) ◽

pp. 553-557 ◽

Cited By ~ 30

Author(s):

Kyle D. Brizendine ◽

Sandra S. Richter ◽

Eric D. Cober ◽

David van Duin

Keyword(s):

Urinary Tract ◽

Klebsiella Pneumoniae ◽

Solid Organ Transplantation ◽

Organ Transplant ◽

Carbapenem Resistance ◽

First Episode ◽

Solid Organ ◽

Content Type ◽

Carbapenem Resistant ◽

Tract Infections

ABSTRACTCarbapenem-resistantKlebsiella pneumoniae(CRKP) is an emerging pathogen with a devastating impact on organ transplant recipients (OTRs). Data describing urinary tract infections (UTIs) due to CRKP, compared to extended-spectrum β-lactamase (ESBL)-producing and susceptibleK. pneumoniae, are lacking. We conducted a retrospective cohort study comparing OTRs with a first episode of UTI due to CRKP, ESBL-producingK. pneumoniae, or susceptibleK. pneumoniae. We identified 108 individuals; 22 (20%) had UTIs due to CRKP, 22 (20%) due to ESBL-producingK. pneumoniae, and 64 (60%) due to susceptibleK. pneumoniae. Compared to susceptibleK. pneumoniae(27%), patients with UTIs due to CRKP or ESBL-producingK. pneumoniaewere more likely to have a ≥24-hour stay in the intensive care unit (ICU) before or after development of the UTI (64% and 77%, respectively;P< 0.001). Among 105/108 hospitalized patients (97%), the median lengths of stay prior to UTI with CRKP or ESBL-producingK. pneumoniae(7 and 8 days, respectively) were significantly longer than that for susceptibleK. pneumoniae(1 day;P< 0.001). Clinical failure was observed for 8 patients (36%) with CRKP, 4 (18%) with ESBL-producingK. pneumoniae, and 9 (14%) with susceptibleK. pneumoniae(P= 0.073). Microbiological failure was seen for 10 patients (45%) with CRKP, compared with 2 (9%) with ESBL-producingK. pneumoniaeand 2 (3%) with susceptibleK. pneumoniae(P< 0.001). In multivariable logistic regression analyses, CRKP was associated with greater odds of microbiological failure (versus ESBL-producingK. pneumoniae: odds ratio [OR], 9.36, 95% confidence interval [CI], 1.94 to 72.1; versus susceptibleK. pneumoniae: OR, 31.4, 95% CI, 5.91 to 264). In conclusion, CRKP is associated with ICU admission, long length of stay, and microbiological failure among OTRs with UTIs. Greater numbers are needed to determine risk factors for infection and differences in meaningful endpoints associated with carbapenem resistance.

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Investigation and management of Klebsiella Pneumoniae Outbreak in Intensive Care Unit of Tanta University Emergency Hospital

10.51429/ejmm30307 ◽

2021 ◽

Vol 30 (3) ◽

pp. 53-58

Author(s):

Sara Youssef Maxwell ◽

Mohamed S. Abd Elghafar ◽

Maii A. Shams Eldeen

Keyword(s):

Intensive Care Unit ◽

Intensive Care ◽

Klebsiella Pneumoniae ◽

Multidrug Resistant ◽

Infection Prevention And Control ◽

Drug Resistant ◽

Emergency Hospital ◽

First Case ◽

Wide Range ◽

Tract Infections

Background: Klebsiella pneumoniae infection is responsible for a wide range of infections including pneumonia, bacteremia, wound infections, and urinary tract infections. Objective: To investigate and manage the occurrence of multi-drug resistant Klebsiella pneumoniae outbreak in Intensive Care Unit of Tanta University Emergency Hospital. Methodology: The investigation of the outbreak included isolates identification and typing while management included implementation of infection prevention and control precautions; establishment of an Outbreak Control Team; epidemiological investigations; and decontamination of environment. Results: During September 2020, five patients in the Intensive Care Unit in Emergency Hospital of Tanta University had multi drug-resistant Klebsiella pneumoniae identified in samples obtained from a variety of specimens. The fifth case was identified 10 days following confirmation of the first case. The Microbiology laboratory confirmed the five cases had identical Klebsiella pneumoniae strains. This suggests that there was a patient-to- patient spread of multidrug resistant Klebsiella pneumoniae. Conclusion: This investigation revealed the importance of proactive recognition of a possible outbreak, screening of patients transferred from other hospitals, early identification of any unusual microorganisms and implementation of early infection control interventions.

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In Vitro Synergism of Colistin and N-acetylcysteine against Stenotrophomonas maltophilia

Antibiotics ◽

10.3390/antibiotics8030101 ◽

2019 ◽

Vol 8 (3) ◽

pp. 101 ◽

Cited By ~ 2

Author(s):

Nagaia Ciacci ◽

Selene Boncompagni ◽

Felice Valzano ◽

Lisa Cariani ◽

Stefano Aliberti ◽

...

Keyword(s):

Stenotrophomonas Maltophilia ◽

Respiratory Infections ◽

Topical Administration ◽

Opportunistic Pathogen ◽

Wide Range ◽

Tract Infections ◽

Human Infections ◽

Time Kill ◽

Dose Dependent

Stenotrophomonas maltophilia is an emerging global opportunistic pathogen, responsible for a wide range of human infections, including respiratory tract infections. Intrinsic multidrug resistance and propensity to form biofilms make S. maltophilia infections recalcitrant to treatment. Colistin is among the second-line options in case of difficult-to-treat S. maltophilia infections, with the advantage of being also administrable by nebulization. We investigated the potential synergism of colistin in combination with N-acetylcysteine (NAC) (a mucolytic agent with antioxidant and anti-inflammatory properties) against S. maltophilia grown in planktonic phase and biofilm. Eighteen S. maltophilia clinical isolates (comprising three isolates from cystic fibrosis (CF) and two trimethoprim-sulfamethoxazole (SXT)-resistant strains) were included. Checkerboard assays showed a synergism of colistin/NAC combinations against the strains with colistin Minimum Inhibitory Concentration (MIC) >2 µg/mL (n = 13), suggesting that NAC could antagonize the mechanisms involved in colistin resistance. Nonetheless, time–kill assays revealed that NAC might potentiate colistin activity also in case of lower colistin MICs. A dose-dependent potentiation of colistin activity by NAC was also clearly observed against S. maltophilia biofilms, also at sub-MIC concentrations. Colistin/NAC combinations, at concentrations likely achievable by topical administration, might represent a valid option for the treatment of S. maltophilia respiratory infections and should be examined further.

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Detection of KPC-2 gene in K. pneumoniae, E. coli and P. mirabilis isolated from Urine sample of Urinary Tract Infection patients

10.53350/pjmhs211572292 ◽

2021 ◽

Vol 15 (7) ◽

pp. 2292-2295

Author(s):

Nargis . ◽

Tayyab ur Rehman ◽

Liaqat Ali ◽

Hanif Khan ◽

Madina .

Keyword(s):

Urinary Tract ◽

Klebsiella Pneumoniae ◽

Antibiotic Sensitivity ◽

Carbapenem Resistance ◽

Urine Samples ◽

Resistant Bacteria ◽

E Coli ◽

Resistance Patterns ◽

Tract Infections ◽

Gene 4

Background: Carbapenem resistance in Enterobacteriaceae is an uprising problem worldwide. KPC is one of the important mechanisms of resistance in Enterobacteriaceae such as K. pneumoniae. Aims and Objectives: The current research focuses on the frequency of the KPC -2 gene in Enterobacteriaceae isolated from urine samples, as well as antibiotic resistance patterns. Methodology: Antibiotic sensitivity patterns were examined on 53 carbapenem-resistant isolates from the Enterobacteriaceae family. These isolates were subjected to the Modified Hodge Test (MHT) and PCR for KPC 2 gene identification. Results: A total of 150 urine samples were processed for the isolation of the most prevalent Enterobacteriaceae. 125 Gram-negative bacterial isolates were obtained in which the consistency of K. pneumonia was 50(40%),E. colin was 55(44%), and P. mirabilis was 20(16%). The test for susceptibility of antibioticresulted that among50 Klebsiella pneumoniae 40% were resistant to Imipenem, while in E. coli 54.4% and P. mirabilis 30 % were resistant to Imipenem respectively. PCR results show the gene KPC-2 out of 15 (75%) 2 (13.2%) Modified Hodge Test Positive Klebsiella pneumoniae isolates. In total 83.3% (n=25) E. coli Modified Hodge Test positive and for the KPC-2 gene 4% were positive. Conclusion:This research demonstrates that in Enterobacteriaceae there isexistence of carbapenem resistance. Surveillance research and complete antibiotic prescription standards should be established at Pakistan's various hospitals to stop the growth of antibiotic-resistant bacteria. Key Words: Enterobacteriaceae, Urinary Tract Infections, Carbapenem, Modified Hodge test

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The Characteristic of Virulence, Biofilm and Antibiotic Resistance of Klebsiella pneumoniae

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph17176278 ◽

2020 ◽

Vol 17 (17) ◽

pp. 6278

Author(s):

Guoying Wang ◽

Guo Zhao ◽

Xiaoyu Chao ◽

Longxiang Xie ◽

Hongju Wang

Keyword(s):

Antibiotic Resistance ◽

Klebsiella Pneumoniae ◽

Resistance Mechanism ◽

Current Medical Research ◽

Opportunistic Pathogen ◽

Multidrug Resistant ◽

Current Medical ◽

Tolerance Mechanisms ◽

Rapid Spread ◽

Tract Infections

Klebsiella pneumoniae is an important gram-negative opportunistic pathogen that causes a variety of infectious diseases, including urinary tract infections, bacteremia, pneumonia, and liver abscesses. With the emergence of multidrug-resistant (MDR) and hypervirulent K. pneumoniae (hvKP) strains, the rapid spread of these clinical strains in geography is particularly worrying. However, the detailed mechanisms of virulence and antibiotic resistance in K. pneumoniae are still not very clear. Therefore, studying and elucidating the pathogenic mechanisms and drug resistance mechanism of K. pneumoniae infection are important parts of current medical research. In this paper, we systematically summarized the virulence, biofilm, and antibiotic tolerance mechanisms of K. pneumoniae, and explored the application of whole genome sequencing and global proteomics, which will provide new clues for clinical treatment of K. pneumoniae.

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

Infection and Immunity ◽

10.1128/iai.05114-11 ◽

2011 ◽

Vol 79 (8) ◽

pp. 3309-3316 ◽

Cited By ~ 140

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.

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A Serendipitous Mutation Reveals the Severe Virulence Defect of a Klebsiella pneumoniae fepB Mutant

mSphere ◽

10.1128/msphere.00341-17 ◽

2017 ◽

Vol 2 (4) ◽

Cited By ~ 12

Author(s):

Michelle Palacios ◽

Christopher A. Broberg ◽

Kimberly A. Walker ◽

Virginia L. Miller

Keyword(s):

Antibiotic Resistance ◽

Urinary Tract ◽

Klebsiella Pneumoniae ◽

Drug Targets ◽

Carbapenem Resistance ◽

Content Type ◽

Hospital Acquired Infections ◽

Tract Infections ◽

Hospital Acquired ◽

Rapid Emergence

ABSTRACT In addition to having a reputation as the causative agent of several types of hospital-acquired infections, Klebsiella pneumoniae has gained widespread attention as a pathogen with a propensity for acquiring antibiotic resistance. It is capable of causing a range of infections, including urinary tract infections, pneumonia, and sepsis. Because of the rapid emergence of carbapenem resistance among Klebsiella strains, there is a dire need for a better understanding of virulence mechanisms and identification of new drug targets. Here, we identify the periplasmic transporter FepB as one such potential target. Klebsiella pneumoniae is considered a significant public health threat because of the emergence of multidrug-resistant strains and the challenge associated with treating life-threatening infections. Capsule, siderophores, and adhesins have been implicated as virulence determinants of K. pneumoniae, yet we lack a clear understanding of how this pathogen causes disease. In a previous screen for virulence genes, we identified a potential new virulence locus and constructed a mutant (smr) with this locus deleted. In this study, we characterize the smr mutant and show that this mutation renders K. pneumoniae avirulent in a pneumonia model of infection. The smr mutant was expected to have a deletion of three genes, but subsequent genome sequencing indicated that a much larger deletion had occurred. Further analysis of the deleted region indicated that the virulence defect of the smr mutant could be attributed to the loss of FepB, a periplasmic protein required for import of the siderophore enterobactin. Interestingly, a ΔfepB mutant was more attenuated than a mutant unable to synthesize enterobactin, suggesting that additional processes are affected. As FepB is highly conserved among the members of the family Enterobacteriaceae, therapeutic targeting of FepB may be useful for the treatment of Klebsiella and other bacterial infections. IMPORTANCE In addition to having a reputation as the causative agent of several types of hospital-acquired infections, Klebsiella pneumoniae has gained widespread attention as a pathogen with a propensity for acquiring antibiotic resistance. It is capable of causing a range of infections, including urinary tract infections, pneumonia, and sepsis. Because of the rapid emergence of carbapenem resistance among Klebsiella strains, there is a dire need for a better understanding of virulence mechanisms and identification of new drug targets. Here, we identify the periplasmic transporter FepB as one such potential target.

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Klebsiella pneumoniae Siderophores Induce Inflammation, Bacterial Dissemination, and HIF-1α Stabilization during Pneumonia

mBio ◽

10.1128/mbio.01397-16 ◽

2016 ◽

Vol 7 (5) ◽

Cited By ~ 57

Author(s):

Victoria I. Holden ◽

Paul Breen ◽

Sébastien Houle ◽

Charles M. Dozois ◽

Michael A. Bachman

Keyword(s):

Klebsiella Pneumoniae ◽

Bacterial Growth ◽

Hypoxia Inducible Factor ◽

Host Protein ◽

Iron Chelators ◽

Bacterial Invasion ◽

Bacterial Dissemination ◽

Wide Range ◽

Tract Infections

ABSTRACT Klebsiella pneumoniae is a Gram-negative pathogen responsible for a wide range of infections, including pneumonia and bacteremia, and is rapidly acquiring antibiotic resistance. K. pneumoniae requires secretion of siderophores, low-molecular-weight, high-affinity iron chelators, for bacterial replication and full virulence. The specific combination of siderophores secreted by K. pneumoniae during infection can impact tissue localization, systemic dissemination, and host survival. However, the effect of these potent iron chelators on the host during infection is unknown. In vitro , siderophores deplete epithelial cell iron, induce cytokine secretion, and activate the master transcription factor hypoxia inducible factor-1α (HIF-1α) protein that controls vascular permeability and inflammatory gene expression. Therefore, we hypothesized that siderophore secretion by K. pneumoniae directly contributes to inflammation and bacterial dissemination during pneumonia. To examine the effects of siderophore secretion independently of bacterial growth, we performed infections with tonB mutants that persist in vivo but are deficient in siderophore import. Using a murine model of pneumonia, we found that siderophore secretion by K. pneumoniae induces the secretion of interleukin-6 (IL-6), CXCL1, and CXCL2, as well as bacterial dissemination to the spleen, compared to siderophore-negative mutants at an equivalent bacterial number. Furthermore, we determined that siderophore-secreting K. pneumoniae stabilized HIF-1α in vivo and that bacterial dissemination to the spleen required alveolar epithelial HIF-1α. Our results indicate that siderophores act directly on the host to induce inflammatory cytokines and bacterial dissemination and that HIF-1α is a susceptibility factor for bacterial invasion during pneumonia. IMPORTANCE Klebsiella pneumoniae causes a wide range of bacterial diseases, including pneumonia, urinary tract infections, and sepsis. To cause infection, K. pneumoniae steals iron from its host by secreting siderophores, small iron-chelating molecules. Classically, siderophores are thought to worsen infections by promoting bacterial growth. In this study, we determined that siderophore-secreting K. pneumoniae causes lung inflammation and bacterial dissemination to the bloodstream independently of bacterial growth. Furthermore, we determined that siderophore-secreting K. pneumoniae activates a host protein, hypoxia inducible factor (HIF)-1α, and requires it for siderophore-dependent bacterial dissemination. Although HIF-1α can protect against some infections, it appears to worsen infection with K. pneumoniae . Together, these results indicate that bacterial siderophores directly alter the host response to pneumonia in addition to providing iron for bacterial growth. Therapies that disrupt production of siderophores could provide a two-pronged attack against K. pneumoniae infection by preventing bacterial growth and preventing bacterial dissemination to the blood.

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