INSIGHTS INTO THE VIRULENCE FACTORS OF ACINETOBACTER BAUMANNII AND THEIR ROLES IN PERSISTENCE AND INFECTIOUS PROCESS

Acinetobacter baumannii is a Gram-negative opportunistic pathogen, which is responsible for a significant and ever-increasing number of health care associated severe infections (such as pneumonia, sepsis, meningitis, wound and urinary tract infections), mainly in severely ill patients. With only a limited number of “traditional” virulence factors, the mechanisms underlying the success of this opportunistic and nosocomial pathogen remain of great interest. With the advent of whole genome sequencing and bioinformatic analysis, some virulence features, including motility, iron-acquisition systems, biofilm development, capsule production, porins, and enzymes, among others have been described. The main purpose of this minireview was to present an update on the main virulence markers of A. baumannii strains and their role in the persistence, infection process and modulation of host immune response.

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Lon Protease Has Multifaceted Biological Functions inAcinetobacter baumannii

Journal of Bacteriology ◽

10.1128/jb.00536-18 ◽

2018 ◽

Vol 201 (2) ◽

Cited By ~ 5

Author(s):

Carly Ching ◽

Brendan Yang ◽

Chineme Onwubueke ◽

David Lazinski ◽

Andrew Camilli ◽

...

Keyword(s):

Acinetobacter Baumannii ◽

Biofilm Formation ◽

Developmental Process ◽

Cell Envelope ◽

Opportunistic Pathogen ◽

Lon Protease ◽

Content Type ◽

Hospital Acquired Infections ◽

Biofilm Development ◽

Hospital Acquired

ABSTRACTAcinetobacter baumanniiis a Gram-negative opportunistic pathogen that is known to survive harsh environmental conditions and is a leading cause of hospital-acquired infections. Specifically, multicellular communities (known as biofilms) ofA. baumanniican withstand desiccation and survive on hospital surfaces and equipment. Biofilms are bacteria embedded in a self-produced extracellular matrix composed of proteins, sugars, and/or DNA. Bacteria in a biofilm are protected from environmental stresses, including antibiotics, which provides the bacteria with selective advantage for survival. Although some gene products are known to play roles in this developmental process inA. baumannii, mechanisms and signaling remain mostly unknown. Here, we find that Lon protease inA. baumanniiaffects biofilm development and has other important physiological roles, including motility and the cell envelope. Lon proteases are found in all domains of life, participating in regulatory processes and maintaining cellular homeostasis. These data reveal the importance of Lon protease in influencing keyA. baumanniiprocesses to survive stress and to maintain viability.IMPORTANCEAcinetobacter baumanniiis an opportunistic pathogen and is a leading cause of hospital-acquired infections.A. baumanniiis difficult to eradicate and to manage, because this bacterium is known to robustly survive desiccation and to quickly gain antibiotic resistance. We sought to investigate biofilm formation inA. baumannii, since much remains unknown about biofilm formation in this bacterium. Biofilms, which are multicellular communities of bacteria, are surface attached and difficult to eliminate from hospital equipment and implanted devices. Our research identifies multifaceted physiological roles for the conserved bacterial protease Lon inA. baumannii. These roles include biofilm formation, motility, and viability. This work broadly affects and expands understanding of the biology ofA. baumannii, which will permit us to find effective ways to eliminate the bacterium.

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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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Insights into Acinetobacter baumannii: A Review of Microbiological, Virulence, and Resistance Traits in a Threatening Nosocomial Pathogen

Antibiotics ◽

10.3390/antibiotics9030119 ◽

2020 ◽

Vol 9 (3) ◽

pp. 119 ◽

Cited By ~ 12

Author(s):

Carole Ayoub Moubareck ◽

Dalal Hammoudi Halat

Keyword(s):

Acinetobacter Baumannii ◽

Virulence Factors ◽

Efflux Pump ◽

Iron Acquisition ◽

Multidrug Resistant ◽

Resistance Mechanisms ◽

Biofilm Production ◽

Resistant Phenotype ◽

Severe Infections ◽

Hydrolyzing Enzymes

Being a multidrug-resistant and an invasive pathogen, Acinetobacter baumannii is one of the major causes of nosocomial infections in the current healthcare system. It has been recognized as an agent of pneumonia, septicemia, meningitis, urinary tract and wound infections, and is associated with high mortality. Pathogenesis in A. baumannii infections is an outcome of multiple virulence factors, including porins, capsules, and cell wall lipopolysaccharide, enzymes, biofilm production, motility, and iron-acquisition systems, among others. Such virulence factors help the organism to resist stressful environmental conditions and enable development of severe infections. Parallel to increased prevalence of infections caused by A. baumannii, challenging and diverse resistance mechanisms in this pathogen are well recognized, with major classes of antibiotics becoming minimally effective. Through a wide array of antibiotic-hydrolyzing enzymes, efflux pump changes, impermeability, and antibiotic target mutations, A. baumannii models a unique ability to maintain a multidrug-resistant phenotype, further complicating treatment. Understanding mechanisms behind diseases, virulence, and resistance acquisition are central to infectious disease knowledge about A. baumannii. The aims of this review are to highlight infections and disease-producing factors in A. baumannii and to touch base on mechanisms of resistance to various antibiotic classes.

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Urothelial Cultures Support Intracellular Bacterial Community Formation by Uropathogenic Escherichia coli

Infection and Immunity ◽

10.1128/iai.00323-09 ◽

2009 ◽

Vol 77 (7) ◽

pp. 2762-2772 ◽

Cited By ~ 72

Author(s):

Ruth E. Berry ◽

David J. Klumpp ◽

Anthony J. Schaeffer

Keyword(s):

Escherichia Coli ◽

Fluorescence Microscopy ◽

Virulence Factors ◽

Biochemical Characterization ◽

Iron Acquisition ◽

Urothelial Cells ◽

Bacterial Aggregates ◽

Tract Infections ◽

Intracellular Proliferation

ABSTRACT Uropathogenic Escherichia coli (UPEC) causes most community-acquired and nosocomial urinary tract infections (UTI). In a mouse model of UTI, UPEC invades superficial bladder cells and proliferates rapidly, forming biofilm-like structures called intracellular bacterial communities (IBCs). Using a gentamicin protection assay and fluorescence microscopy, we developed an in vitro model for studying UPEC proliferation within immortalized human urothelial cells. By pharmacologic manipulation of urothelial cells with the cholesterol-sequestering drug filipin, numbers of intracellular UPEC CFU increased 8 h and 24 h postinfection relative to untreated cultures. Enhanced UPEC intracellular proliferation required that the urothelial cells, but not the bacteria, be filipin treated prior to infection. However, neither UPEC frequency of invasion nor early intracellular trafficking events to a Lamp1-positive compartment were modulated by filipin. Upon inspection by fluorescence microscopy, cultures with enhanced UPEC intracellular proliferation exhibited large, dense bacterial aggregates within cells that resembled IBCs but were contained with Lamp1-positive vacuoles. While an isogenic fimH mutant was capable of forming these IBC-like structures, the mutant formed significantly fewer than wild-type UPEC. Similar to IBCs, expression of E. coli iron acquisition systems was upregulated by intracellular UPEC. Expression of other putative virulence factors, including hlyA, cnf1, fliC, kpsD, and the biofilm adhesin yfaL also increased, while expression of fimA decreased and that of flu did not change. These results indicate that UPEC differentially regulates virulence factors in the intracellular environment. Thus, immortalized urothelial cultures that recapitulate IBC formation in vitro represent a novel system for the molecular and biochemical characterization of the UPEC intracellular life cycle.

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RecA levels modulate biofilm development in Acinetobacter baumannii

10.1101/809392 ◽

2019 ◽

Author(s):

Carly Ching ◽

Paul Muller ◽

Merlin Brychcy ◽

Alicyn Reverdy ◽

Brian Nguyen ◽

...

Keyword(s):

Dna Damage ◽

Acinetobacter Baumannii ◽

Biofilm Formation ◽

Bacterial Infections ◽

Opportunistic Pathogen ◽

Cell Types ◽

Surface Attachment ◽

Damage Response ◽

Fundamental Biology ◽

Biofilm Development

AbstractInfections caused by Acinetobacter baumannii, a Gram-negative opportunistic pathogen, are difficult to eradicate due to the bacterium’s propensity to quickly gain antibiotic resistances and form protective bacterial multicellular communities known as biofilms. The A. baumannii DNA damage response (DDR) mediates antibiotic resistance acquisition and regulates RecA in an atypical fashion; both RecALow and RecAHigh cell types are formed in response to DNA damage. In this study, we show that RecA levels modulate biofilm development, formation and dispersal, through bfmR, the global biofilm regulator. RecA loss results in surface attachment and prominent biofilms while elevated RecA leads to diminished attachment and dispersal. Recalcitrance to treatment may be explained by DDR induction, common during infection, and the balance between biofilm maintenance in low RecA cells, and increased mutagenesis and dispersal to reach new niches in high RecA cells. These data highlight the importance of understanding fundamental biology to better treat bacterial infections.ImpactThe mechanism of biofilm formation and dispersal in A. baumannii, shown here to depend on RecA levels, contributes to the understanding of recalcitrant infections caused by this important pathogen.

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Virulence and Antibiotic Resistance of Acinetobacter baumannii among Urinary Tract Infections

10.5772/intechopen.94508 ◽

2020 ◽

Author(s):

Hussein O.M. Al-Dahmoshi ◽

Noor S.K. Al-Khafaji ◽

Farah T. Al-Alaq

Keyword(s):

Antibiotic Resistance ◽

Urinary Tract ◽

Acinetobacter Baumannii ◽

Urinary Tract Infections ◽

Bacterial Infections ◽

Iron Acquisition ◽

Protein A ◽

Community Acquired Pneumonia ◽

Tract Infections ◽

Hospital Acquired

Acinetobacter baumannii is one of the opportunistic bacteria firstly related with the hospital acquired infection influencing primarily to weakening the patient in the ICU. It is sometimes transferred to the patient by transient colonization of hands of the workers of healthcare, and persistence on eco-surfaces. Acinetobacter baumannii inhalation aerosolized through endo-tracheal suctioning of the ventilated patient is widespread among ventilator-related pneumonia (VAP). It is infections mainly associated with ventilator-related pneumonia (VAP), community Acquired Pneumonia (CAP), invasive bacterial infections (IBIs) and UTI (urinary tract infection). It is one of the prominent uropathogens problematic with antibiotic resistance especially carbapenem resistant Acinetobacter baumannii (CRAB). Their colonization of urinary tract and establishment of infection may attributed mainly to set of virulence factors like: Acinetobactin-assisted iron acquisition system, Bap (biofilm-related protein), phospholipase D, Ata (Acinetobacter trimeric autotransporter), chaperone-usher type pilus (Csu), OmpA (outer membrane protein A), and Plasminogen-binding protein (CipA). The common drugs used for treatment Acinetobacter baumannii infections involve polymyxins, glycylcyclines, tetracyclines, mono-bactams, fluoroquinolones, aminoglycosides, antipseudomonal carbapenems, antipseudomonal cephalosporins, and sulbactam. The rates of MDR isolation or also comprehensively the resistant Acinetobacter baumannii are significantly increased and so the combination of two or more (colistin, tigecycline, or colistin-rifampicin combination therapy) drugs is sometimes used to treat infections of MDR-AB. As a conclusion the Acinetobacter baumannii engagement in urinary tract infections attributed mainly to their adhesins, invasins and intrinsic antibiotic resistance.

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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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Proteus mirabilis Genes That Contribute to Pathogenesis of Urinary Tract Infection: Identification of 25 Signature-Tagged Mutants Attenuated at Least 100-Fold

Infection and Immunity ◽

10.1128/iai.72.5.2922-2938.2004 ◽

2004 ◽

Vol 72 (5) ◽

pp. 2922-2938 ◽

Cited By ~ 129

Author(s):

Laurel S. Burall ◽

Janette M. Harro ◽

Xin Li ◽

C.Virginia Lockatell ◽

Stephanie D. Himpsl ◽

...

Keyword(s):

Urinary Tract ◽

Mouse Model ◽

Virulence Factors ◽

Proteus Mirabilis ◽

Parent Strain ◽

Iron Acquisition ◽

Phosphate Transport ◽

Transposon Mutants ◽

Cell Surface Structure ◽

Tract Infections

ABSTRACT Proteus mirabilis, a common cause of urinary tract infections (UTI) in individuals with functional or structural abnormalities or with long-term catheterization, forms bladder and kidney stones as a consequence of urease-mediated urea hydrolysis. Known virulence factors, besides urease, are hemolysin, fimbriae, metalloproteases, and flagella. In this study we utilized the CBA mouse model of ascending UTI to evaluate the colonization of mutants of P. mirabilis HI4320 that were generated by signature-tagged mutagenesis. By performing primary screening of 2,088 P. mirabilis transposon mutants, we identified 502 mutants that ranged from slightly attenuated to unrecoverable. Secondary screening of these mutants revealed that 114 transposon mutants were reproducibly attenuated. Cochallenge of 84 of these single mutants with the parent strain in the mouse model resulted in identification of 37 consistently out-competed P. mirabilis transposon mutants, 25 of which were out-competed >100-fold for colonization of the bladder and/or kidneys by the parent strain. We determined the sequence flanking the site of transposon insertion in 29 attenuated mutants and identified genes affecting motility, iron acquisition, transcriptional regulation, phosphate transport, urease activity, cell surface structure, and key metabolic pathways as requirements for P. mirabilis infection of the urinary tract. Two mutations localized to a ∼42-kb plasmid present in the parent strain, suggesting that the plasmid is important for colonization. Isolation of disrupted genes encoding proteins with homologies to known bacterial virulence factors, especially the urease accessory protein UreF and the disulfide formation protein DsbA, showed that the CBA mouse model and mutant pools are a reliable source of attenuated mutants with mutations in virulence genes.

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The Toxin-Antitoxin Systems of the Opportunistic Pathogen Stenotrophomonas maltophilia of Environmental and Clinical Origin

Toxins ◽

10.3390/toxins12100635 ◽

2020 ◽

Vol 12 (10) ◽

pp. 635

Author(s):

Laurita Klimkaitė ◽

Julija Armalytė ◽

Jūratė Skerniškytė ◽

Edita Sužiedėlienė

Keyword(s):

Biofilm Formation ◽

Stenotrophomonas Maltophilia ◽

Opportunistic Pathogen ◽

Bioinformatic Analysis ◽

Multidrug Resistant ◽

Bacterial Toxin ◽

Clinical Settings ◽

Environmental Bacterium ◽

Tract Infections

Stenotrophomonas maltophilia is a ubiquitous environmental bacterium that has recently emerged as a multidrug-resistant opportunistic pathogen causing bloodstream, respiratory, and urinary tract infections. The connection between the commensal environmental S. maltophilia and the opportunistic pathogen strains is still under investigation. Bacterial toxin–antitoxin (TA) systems have been previously associated with pathogenic traits, such as biofilm formation and resistance to antibiotics, which are important in clinical settings. The same species of the bacterium can possess various sets of TAs, possibly influencing their overall stress response. While the TA systems of other important opportunistic pathogens have been researched, nothing is known about the TA systems of S. maltophilia. Here, we report the identification and characterization of S. maltophilia type II TA systems and their prevalence in the isolates of clinical and environmental origins. We found 49 putative TA systems by bioinformatic analysis in S. maltophilia genomes. Despite their even spread in sequenced S. maltophilia genomes, we observed that relBE, hicAB, and previously undescribed COG3832-ArsR operons were present solely in clinical S. maltophilia isolates collected in Lithuania, while hipBA was more frequent in the environmental ones. The kill-rescue experiments in Escherichia coli proved higBA, hicAB, and relBE systems to be functional TA modules. Together with different TA profiles, the clinical S. maltophilia isolates exhibited stronger biofilm formation, increased antibiotic, and serum resistance compared to environmental isolates. Such tendencies suggest that certain TA systems could be used as indicators of virulence traits.

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Virulence Potential and Treatment Options of Multidrug-Resistant (MDR) Acinetobacter baumannii

Microorganisms ◽

10.3390/microorganisms9102104 ◽

2021 ◽

Vol 9 (10) ◽

pp. 2104

Author(s):

Sunil Kumar ◽

Razique Anwer ◽

Arezki Azzi

Keyword(s):

Acinetobacter Baumannii ◽

Virulence Factors ◽

Bacterial Infections ◽

Antimicrobial Agents ◽

Treatment Options ◽

Outer Membrane Proteins ◽

Multidrug Resistant ◽

High Rate ◽

World Health ◽

Tract Infections

Acinetobacter baumannii is an opportunistic pathogen which is undoubtedly known for a high rate of morbidity and mortality in hospital-acquired infections. A. baumannii causes life-threatening infections, including; ventilator-associated pneumonia (VAP), meningitis, bacteremia, and wound and urinary tract infections (UTI). In 2017, the World Health Organization listed A. baumannii as a priority-1 pathogen. The prevalence of A. baumannii infections and outbreaks emphasizes the direct need for the use of effective therapeutic agents for treating such infections. Available antimicrobials, such as; carbapenems, tigecycline, and colistins have insufficient effectiveness due to the appearance of multidrug-resistant strains, accentuating the need for alternative and novel therapeutic remedies. To understand and overcome this menace, the knowledge of recent discoveries on the virulence factors of A. baumannii is needed. Herein, we summarized the role of various virulence factors, including; outer membrane proteins, efflux pumps, biofilm, penicillin-binding proteins, and siderophores/iron acquisition systems. We reviewed the recent scientific literature on different A. baumannii virulence factors and the effective antimicrobial agents for the treatment and management of bacterial infections.

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