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Dysregulation of Escherichia coli α-hemolysin expression alters the course of acute and persistent urinary tract infection.
Nagamatsu K, Hannan TJ, Guest RL, Kostakioti M, Hadjifrangiskou M, Binkley J, Dodson K, Raivio TL, Hultgren SJ
(2015) Proc Natl Acad Sci U S A 112: E871-80
MeSH Terms: Acute Disease, Animals, Apoptosis, Bacterial Proteins, Carrier Proteins, Caspase 1, Chronic Disease, Colony Count, Microbial, Disease Progression, Enzyme Activation, Escherichia coli Infections, Escherichia coli Proteins, Female, Gene Expression Regulation, Bacterial, Hemolysin Proteins, Humans, Inflammasomes, Interleukin-1beta, Mice, Models, Biological, NLR Family, Pyrin Domain-Containing 3 Protein, Signal Transduction, Urinary Bladder, Urinary Tract Infections, Uropathogenic Escherichia coli, Virulence
Show Abstract · Added February 16, 2016
Urinary tract infections (UTIs) are among the most common bacterial infections, causing considerable morbidity in females. Infection is highly recurrent despite appropriate antibiotic treatment. Uropathogenic Escherichia coli (UPEC), the most common causative agent of UTIs, invades bladder epithelial cells (BECs) and develops into clonal intracellular bacterial communities (IBCs). Upon maturation, IBCs disperse, with bacteria spreading to neighboring BECs to repeat this cycle. This process allows UPEC to gain a foothold in the face of innate defense mechanisms, including micturition, epithelial exfoliation, and the influx of polymorphonuclear leukocytes. Here, we investigated the mechanism and dynamics of urothelial exfoliation in the early acute stages of infection. We show that UPEC α-hemolysin (HlyA) induces Caspase-1/Caspase-4-dependent inflammatory cell death in human urothelial cells, and we demonstrate that the response regulator (CpxR)-sensor kinase (CpxA) two-component system (CpxRA), which regulates virulence gene expression in response to environmental signals, is critical for fine-tuning HlyA cytotoxicity. Deletion of the cpxR transcriptional response regulator derepresses hlyA expression, leading to enhanced Caspase-1/Caspase-4- and NOD-like receptor family, pyrin domain containing 3-dependent inflammatory cell death in human urothelial cells. In vivo, overexpression of HlyA during acute bladder infection induces more rapid and extensive exfoliation and reduced bladder bacterial burdens. Bladder fitness is restored fully by inhibition of Caspase-1 and Caspase-11, the murine homolog of Caspase-4. Thus, we have discovered that fine-tuning of HlyA expression by the CpxRA system is critical for enhancing UPEC fitness in the urinary bladder. These results have significant implications for our understanding of how UPEC establishes persistent colonization.
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26 MeSH Terms
Secreted Gaussia princeps luciferase as a reporter of Escherichia coli replication in a mouse tissue cage model of infection.
Liu M, Blinn C, McLeod SM, Wiseman JW, Newman JV, Fisher SL, Walkup GK
(2014) PLoS One 9: e90382
MeSH Terms: Animals, Biocatalysis, Chromosomes, Bacterial, Colony Count, Microbial, Copepoda, Disease Models, Animal, Erwinia, Escherichia coli, Escherichia coli Infections, Genes, Reporter, Genetic Loci, Imaging, Three-Dimensional, Luciferases, Luminescence, Mice, Polysaccharide-Lyases
Show Abstract · Added March 20, 2014
Measurement of bacterial burden in animal infection models is a key component for both bacterial pathogenesis studies and therapeutic agent research. The traditional quantification means for in vivo bacterial burden requires frequent animal sacrifice and enumerating colony forming units (CFU) recovered from infection loci. To address these issues, researchers have developed a variety of luciferase-expressing bacterial reporter strains to enable bacterial detection in living animals. To date, all such luciferase-based bacterial reporters are in cell-associated form. Production of luciferase-secreting recombinant bacteria could provide the advantage of reporting CFU from both infection loci themselves and remote sampling (eg. body fluid and plasma). Toward this end, we have genetically manipulated a pathogenic Escherichia coli (E. coli) strain, ATCC25922, to secrete the marine copepod Gaussia princeps luciferase (Gluc), and assessed the use of Gluc as both an in situ and ex situ reporter for bacterial burden in mouse tissue cage infections. The E. coli expressing Gluc demonstrates in vivo imaging of bacteria in a tissue cage model of infection. Furthermore, secreted Gluc activity and bacterial CFUs recovered from tissue cage fluid (TCF) are correlated along 18 days of infection. Importantly, secreted Gluc can also be detected in plasma samples and serve as an ex situ indicator for the established tissue cage infection, once high bacterial burdens are achieved. We have demonstrated that Gluc from marine eukaryotes can be stably expressed and secreted by pathogenic E. coli in vivo to enable a facile tool for longitudinal evaluation of persistent bacterial infection.
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16 MeSH Terms
Temperature affects the tripartite interactions between bacteriophage WO, Wolbachia, and cytoplasmic incompatibility.
Bordenstein SR, Bordenstein SR
(2011) PLoS One 6: e29106
MeSH Terms: Animals, Bacteriophages, Colony Count, Microbial, Cytoplasm, Models, Biological, Penetrance, Wasps, Wolbachia
Show Abstract · Added October 8, 2015
Wolbachia infections are a model for understanding intracellular, bacterial symbioses. While the symbiosis is often studied from a binary perspective of host and bacteria, it is increasingly apparent that additional trophic levels can influence the symbiosis. For example, Wolbachia in arthropods harbor a widespread temperate bacteriophage, termed WO, that forms virions and rampantly transfers between coinfections. Here we test the hypothesis that temperatures at the extreme edges of an insect's habitable range alter bacteriophage WO inducibility and in turn, Wolbachia densities and the penetrance of cytoplasmic incompatibility. We report four key findings using the model wasp, Nasonia vitripennis: First, both cold treatment at 18 C and heat treatment at 30 C reduce Wolbachia densities by as much as 74% relative to wasps reared at 25 C. Second, in all cases where Wolbachia densities decline due to temperature changes, phage WO densities increase and inversely associate with Wolbachia densities. Heat has a marked effect on phage WO, yielding phage densities that are 552% higher than the room temperature control. Third, there is a significant affect of insect family on phage WO and endoysmbiont densities. Fourth, at extreme temperatures, there was a temperature-mediated adjustment to the density threshold at which Wolbachia cause complete cytoplasmic incompatibility. Taken together, these results demonstrate that temperature simultaneously affects phage WO densities, endosymbiont densities, and the penetrance of cytoplasmic incompatibility. While temperature shock enhances bacteriophage inducibility and the ensuing bacterial mortality in a wide range of medically and industrially-important bacteria, this is the first investigation of the associations in an obligate intracellular bacteria. Implications to a SOS global sensing feedback mechanism in Wolbachia are discussed.
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8 MeSH Terms
Cationic amino acid transporter 2 enhances innate immunity during Helicobacter pylori infection.
Barry DP, Asim M, Scull BP, Piazuelo MB, de Sablet T, Lewis ND, Coburn LA, Singh K, Ellies LG, Gobert AP, Chaturvedi R, Wilson KT
(2011) PLoS One 6: e29046
MeSH Terms: Acute Disease, Amino Acid Transport Systems, Basic, Animals, Cell Count, Chronic Disease, Colony Count, Microbial, Dendritic Cells, Gastritis, Helicobacter Infections, Helicobacter pylori, Immunity, Innate, Interleukin-12, Macrophages, Mice, Nitric Oxide Synthase Type II, Stomach, Th1 Cells, Th2 Cells
Show Abstract · Added March 5, 2014
Once acquired, Helicobacter pylori infection is lifelong due to an inadequate innate and adaptive immune response. Our previous studies indicate that interactions among the various pathways of arginine metabolism in the host are critical determinants of outcomes following infection. Cationic amino acid transporter 2 (CAT2) is essential for transport of L-arginine (L-Arg) into monocytic immune cells during H. pylori infection. Once within the cell, this amino acid is utilized by opposing pathways that lead to elaboration of either bactericidal nitric oxide (NO) produced from inducible NO synthase (iNOS), or hydrogen peroxide, which causes macrophage apoptosis, via arginase and the polyamine pathway. Because of its central role in controlling L-Arg availability in macrophages, we investigated the importance of CAT2 in vivo during H. pylori infection. CAT2(-/-) mice infected for 4 months exhibited decreased gastritis and increased levels of colonization compared to wild type mice. We observed suppression of gastric macrophage levels, macrophage expression of iNOS, dendritic cell activation, and expression of granulocyte-colony stimulating factor in CAT2(-/-) mice suggesting that CAT2 is involved in enhancing the innate immune response. In addition, cytokine expression in CAT2(-/-) mice was altered from an antimicrobial Th1 response to a Th2 response, indicating that the transporter has downstream effects on adaptive immunity as well. These findings demonstrate that CAT2 is an important regulator of the immune response during H. pylori infection.
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18 MeSH Terms
Intrapulmonary administration of leukotriene B4 enhances pulmonary host defense against pneumococcal pneumonia.
Mancuso P, Lewis C, Serezani CH, Goel D, Peters-Golden M
(2010) Infect Immun 78: 2264-71
MeSH Terms: Administration, Inhalation, Aerosols, Animals, Arachidonate 5-Lipoxygenase, Biological Products, Colony Count, Microbial, Cytokines, Immunologic Factors, Injections, Intraperitoneal, Injections, Intravenous, Leukocyte Count, Leukotriene B4, Lung, Mice, Mice, Knockout, Pneumonia, Pneumococcal, Streptococcus pneumoniae
Show Abstract · Added May 4, 2017
Leukotriene B(4) (LTB(4)) is a potent lipid mediator of inflammation formed by the 5-lipoxygenase (5-LO)-catalyzed oxidation of arachidonic acid. We have previously shown that (i) LTB(4) is generated during infection, (ii) its biosynthesis is essential for optimal antimicrobial host defense, (iii) LT deficiency is associated with clinical states of immunocompromise, and (iv) exogenous LTB(4) augments antimicrobial functions in phagocytes. Here, we sought to determine whether the administration of LTB(4) has therapeutic potential in a mouse model of pneumonia. Wild-type and 5-LO knockout mice were challenged with Streptococcus pneumoniae via the intranasal route, and bacterial burdens, leukocyte counts, and cytokine levels were determined. LTB(4) was administered via the intraperitoneal, intravenous, and intranasal routes prior to pneumococcal infection and by aerosol 24 h following infection. Leukocytes recovered from mice given S. pneumoniae and treated with aerosolized LTB(4) were evaluated for expression levels of the p47phox subunit of NADPH oxidase. Intrapulmonary but not systemic pretreatment with LTB(4) significantly reduced the lung S. pneumoniae burden in wild-type mice. Aerosolized LTB(4) was effective at improving lung bacterial clearance when administered postinoculation in animals with established infection and exhibited greater potency in 5-LO knockout animals, which also exhibited greater baseline susceptibility. Augmented bacterial clearance in response to LTB(4) was associated with enhanced monocyte recruitment and leukocyte expression of p47phox. The results of the current study in an animal model serve as a proof of concept for the potential utility of treatment with aerosolized LTB(4) as an immunostimulatory strategy in patients with bacterial pneumonia.
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17 MeSH Terms
Inactivation of phospholipase D diminishes Acinetobacter baumannii pathogenesis.
Jacobs AC, Hood I, Boyd KL, Olson PD, Morrison JM, Carson S, Sayood K, Iwen PC, Skaar EP, Dunman PM
(2010) Infect Immun 78: 1952-62
MeSH Terms: Acinetobacter Infections, Acinetobacter baumannii, Amino Acid Sequence, Animal Structures, Animals, Bacterial Proteins, Colony Count, Microbial, DNA Transposable Elements, Epithelial Cells, Histocytochemistry, Humans, Mice, Mice, Inbred C57BL, Microscopy, Molecular Sequence Data, Mutagenesis, Insertional, Phospholipase D, Pneumonia, Bacterial, Serum, Virulence, Virulence Factors
Show Abstract · Added March 20, 2014
Acinetobacter baumannii is an emerging bacterial pathogen of considerable health care concern. Nonetheless, relatively little is known about the organism's virulence factors or their regulatory networks. Septicemia and ventilator-associated pneumonia are two of the more severe forms of A. baumannii disease. To identify virulence factors that may contribute to these disease processes, genetically diverse A. baumannii clinical isolates were evaluated for the ability to proliferate in human serum. A transposon mutant library was created in a strain background that propagated well in serum and screened for members with decreased serum growth. The results revealed that disruption of A. baumannii phospholipase D (PLD) caused a reduction in the organism's ability to thrive in serum, a deficiency in epithelial cell invasion, and diminished pathogenesis in a murine model of pneumonia. Collectively, these results suggest that PLD is an A. baumannii virulence factor.
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21 MeSH Terms
QseC-mediated dephosphorylation of QseB is required for expression of genes associated with virulence in uropathogenic Escherichia coli.
Kostakioti M, Hadjifrangiskou M, Pinkner JS, Hultgren SJ
(2009) Mol Microbiol 73: 1020-31
MeSH Terms: Animals, Bacterial Proteins, Colony Count, Microbial, Escherichia coli, Escherichia coli Infections, Escherichia coli Proteins, Female, Fimbriae, Bacterial, Flagella, Gene Expression Regulation, Bacterial, Kidney, Mice, Mice, Inbred C3H, Models, Biological, Urinary Bladder, Urinary Tract Infections, Virulence, Virulence Factors
Show Abstract · Added August 6, 2014
Bacteria sense environmental cues and regulate gene expression accordingly so as to persist in diverse niches. QseC is a membrane sensor kinase shown in enterohemorrhagic Escherichia coli to respond to host and bacterial signals by phosphorylating the QseB response regulator at residue D51, resulting in QseB activation and presumably upregulation of virulence genes. We studied QseBC in uropathogenic E. coli (UPEC). UPEC establish infection by colonizing and invading bladder cells. After invasion, UPEC can escape into the cytoplasm where they can form intracellular bacterial communities. Deletion of qseC significantly attenuated intracellular bacterial community formation and virulence, whereas paradoxically qseB deletion did not impact pathogenesis. We found that QseB upregulates its own expression in the qseC mutant, arguing that it is activated even in the absence of QseC. However, expression of QseB, but not a QseB_D51A mutant, in the absence of QseC resulted in downregulation of type 1 pili, curli and flagella. We observed similar phenotypes with enterohemorrhagic E. coli, showing that this is not a UPEC-specific phenomenon. Target gene expression is restored when QseC is present. We discovered that QseC has phosphatase activity required for QseB dephosphorylation. Thus, the QseC phosphatase capacity is critical for modulating QseB activity and subsequent gene expression.
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18 MeSH Terms
CD4+ T-cell depletion is not associated with alterations in survival, bacterial clearance, and inflammation after cecal ligation and puncture.
Enoh VT, Lin SH, Etogo A, Lin CY, Sherwood ER
(2008) Shock 29: 56-64
MeSH Terms: Animals, Bacteria, CD4 Antigens, CD4-Positive T-Lymphocytes, Colony Count, Microbial, Cytokines, Female, Inflammation, Killer Cells, Natural, Lymphocyte Depletion, Mice, Mice, Inbred C57BL, Mice, Knockout, Sepsis
Show Abstract · Added October 18, 2015
Our recent studies indicate that mice depleted of T cells that bear the alphabeta T-cell receptor (alphabeta T cells) show less inflammation, less physiological dysfunction, and improved survival after cecal ligation and puncture (CLP) compared with control mice. Classic CD4(+) and CD8(+) T cells comprise most of the alphabeta T-cell population. We previously showed that CD8(+) T cells, in conjunction with natural killer (NK) cells, participate in CLP-induced inflammation. However, the contribution of CD4(+) T cells to the early inflammatory response caused by CLP is largely undefined. In the present study, we evaluated CLP-induced mortality, bacterial clearance, and inflammation in mice that were depleted of CD4(+) T cells. Compared with control mice, CD4 knockout mice and wild-type mice treated with anti-CD4 did not show significant differences in survival, cytokine production, and systemic bacterial counts. The combined depletion of CD4(+) T and NK cells resulted in improved survival and decreased cytokine production compared with mice possessing a full lymphocyte complement, especially when CD4(+) T and NK cell-deficient mice were treated with imipenem. These improvements were nearly identical to those observed in mice depleted only of NK cells. These studies show that CD4(+) T cells do not seem to play a critical role in facilitating the early inflammatory response caused by CLP.
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14 MeSH Terms
Effect of transforming growth factor-beta neutralization on survival and bacterial clearance in a murine model of Pseudomonas aeruginosa burn wound infection.
Huang Z, Pereira C, Toliver-Kinsky T, Murphey ED, Varma TK, Lin CY, Herndon DN, Sherwood ER
(2006) J Burn Care Res 27: 682-7
MeSH Terms: Animals, Antibodies, Burns, Colony Count, Microbial, Female, Lung, Mice, Mice, Inbred C57BL, Models, Animal, Pseudomonas Infections, Pseudomonas aeruginosa, Transforming Growth Factor beta, Wound Infection
Show Abstract · Added October 18, 2015
Transforming growth factor-beta (TGF-beta), a cytokine with anti-inflammatory properties, may contribute to postburn immunosuppression. This study was designed to determine whether neutralizing TGF-beta in burned mice could improve resistance to infection. C57BL/6J mice received a 35% TBSA flame burn under isoflurane anesthesia. Four days after injury, mice were treated with TGF-beta antibody or nonspecific IgG. On day 5 after burn injury, mice were inoculated with Pseudomonas aeruginosa at the burn wound site or received intraperitoneal injection with P. aeruginosa. Mice treated with anti-TGF-beta exhibited significantly improved survival compared with mice treated with nonspecific IgG after challenge with P. aeruginosa at the burn wound site or after intraperitoneal injection of P. aeruginosa. In mice with burn wound infections, bacterial counts in burn wounds, blood, and lung were decreased in mice treated with anti-TGF-beta compared with mice treated with control IgG. Bacterial counts in lung and blood after intraperitoneal challenge with P. aeruginosa also were significantly lower in burned mice treated with anti-TGF-beta compared with those treated with nonspecific IgG. Our data suggest that neutralization of TGF-beta at 4 days after burn injury in mice improves local and systemic clearance of P. aeruginosa and enhances survival after P. aeruginosa challenge.
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13 MeSH Terms
Role of granulocyte macrophage colony-stimulating factor during gram-negative lung infection with Pseudomonas aeruginosa.
Ballinger MN, Paine R, Serezani CH, Aronoff DM, Choi ES, Standiford TJ, Toews GB, Moore BB
(2006) Am J Respir Cell Mol Biol 34: 766-74
MeSH Terms: Animals, Chemokines, CXC, Colony Count, Microbial, Cytokines, Eicosanoids, Granulocyte-Macrophage Colony-Stimulating Factor, Leukocytes, Lung, Macrophages, Alveolar, Mice, Mice, Inbred C57BL, Mice, Knockout, Phagocytosis, Pneumonia, Bacterial, Pseudomonas Infections, Pseudomonas aeruginosa
Show Abstract · Added May 4, 2017
Granulocyte macrophage colony-stimulating factor (GM-CSF) stimulates survival, proliferation, differentiation, and function of myeloid cells. Recently, GM-CSF has been shown to be important for normal pulmonary homeostasis. We report that GM-CSF is induced in lung leukocytes during infection with Gram-negative bacteria. Therefore, we postulated that deficiencies in GM-CSF would increase susceptibility to Gram-negative infection in vivo. After an intratracheal inoculum with Pseudomonas aeruginosa, GM-CSF-/- mice show decreased survival compared with wild-type mice. GM-CSF-/- mice show increased lung, spleen, and blood bacterial CFU. GM-CSF-/- mice are defective in the production of cysteinyl leukotrienes, prostaglandin E2, macrophage inflammatory protein, and keratinocyte-derived chemokine in lung leukocytes postinfection. Despite these defects, inflammatory cell recruitment is not diminished at 6 or 24 h postinfection, and the functional activity of polymorphonuclear leukocytes from the lung and peritoneum against P. aeruginosa is enhanced in GM-CSF-/- mice. In contrast, alveolar macrophage (AM) phagocytosis, killing, and H2O2 production are defective in GM-CSF-/- mice. Although the absence of GM-CSF has profound effects on AMs, peritoneal macrophages seem to have normal bactericidal activities in GM-CSF-/- mice. Defects in AM function may be related to diminished levels of IFN-gamma and TNF-alpha postinfection. Thus, GM-CSF-/- mice are more susceptible to lung infection with P. aeruginosa as a result of impaired AM function.
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16 MeSH Terms