bluuebunny/crossref_metadata_2025_split huggingface dataset:
Switch from Enfuvirtide to Raltegravir Lowers Plasma Concentrations of Darunavir and Tipranavir: a Pharmacokinetic Substudy of the EASIER-ANRS 138 Trial
Authors: Goldwirt Lauriane , Braun Joséphine , de Castro Nathalie , Charreau Isabelle , Barrail-Tran Aurélie , Delaugerre Constance , Raffi François , Lascoux-Combe Caroline , Aboulker Jean-Pierre , Taburet Anne-Marie , Molina Jean-Michel 
Published: May 2011

ABSTRACTWe compared tipranavir and darunavir concentrations measured at steady state in 20 human immunodeficiency virus (HIV)-infected patients enrolled in the EASIER-ANRS 138 clinical trial who switched from enfuvirtide to raltegravir while maintaining the same background regimen. The geometric mean ratios of the observed predose concentration (Ctrough), maximum concentration of drug observed in plasma (Cmax), and area under the plasma concentration-time curve (AUC) before (day 0) and after (week 24) the switch were 0.49, 0.76, and 0.67 and 0.82, 0.68, and 0.64 for tipranavir and darunavir, respectively. The virologic consequences of these drug interactions have yet to be determined.
Early MyD88-Dependent Induction of Interleukin-17A Expression during Salmonella Colitis
Authors: Keestra A. Marijke , Godinez Ivan , Xavier Mariana N. , Winter Maria G. , Winter Sebastian E. , Tsolis Renée M. , Bäumler Andreas J. 
Published: May 2011

ABSTRACT

The development of T helper 17 (T
H
17) cells is a well-established adaptive mechanism for the production of interleukin-17A (IL-17A), a cytokine involved in neutrophil recruitment. However, pathways contributing to mucosal expression of IL-17A during the initial phase of a bacterial infection have received less attention. Here we used the mouse colitis model of
Salmonella enterica
serotype Typhimurium infection to investigate the contribution of myeloid differentiation primary response protein 88 (MyD88) to inflammation and mucosal IL-17A expression. Expression of IL-23 in the cecal mucosa during
S.
Typhimurium colitis was dependent on the presence of MyD88. Furthermore, initial expression of IL-17A at 24 h after
S.
Typhimurium infection was dependent on MyD88 and the receptor for IL-1β. IL-23 and IL-1β synergized in inducing expression of IL-17A in splenic T cells
in vitro
. In the intestinal mucosa, IL-17A was produced by three distinct T cell populations, including δγ T cells, T
H
17 cells, and CD4
−
CD8
−
T cells. The absence of IL-1β signaling or IL-17 signaling reduced CXC chemokine expression but did not alter the overall severity of pathological lesions in the cecal mucosa. In contrast, cecal pathology and neutrophil recruitment were markedly reduced in Myd88-deficient mice during the initial phases of
S.
Typhimurium infection. Collectively, these data demonstrate that MyD88-dependent mechanisms, including an initial expression of IL-17A, are important for orchestrating early inflammatory responses during
S.
Typhimurium colitis.
Sphingolipid Degradation by Leishmania major Is Required for Its Resistance to Acidic pH in the Mammalian Host
Authors: Xu Wei , Xin Lijun , Soong Lynn , Zhang Kai 
Published: May 2011

ABSTRACTLeishmaniaparasites alternate between flagellated promastigotes in sand flies and nonflagellated amastigotes in mammals, causing a spectrum of serious diseases. To survive, they must resist the harsh conditions in phagocytes (including acidic pH, elevated temperature, and increased oxidative/nitrosative stress) and evade the immune response. Recent studies have highlighted the importance of sphingolipid (SL) metabolism inLeishmaniavirulence. In particular, we have generated aLeishmania majoriscl−mutant which is deficient in SL degradation but grows normally as promastigotes in culture. Importantly,iscl−mutants cannot induce pathology in either immunocompetent or immunodeficient mice yet are able to persist at low levels. In this study, we investigated how the degradation of SLs might contribute toLeishmaniainfection. First, unlike wild-type (WT)L. major,iscl−mutants do not trigger polarized T cell responses in mice. Second, like WT parasites,iscl−mutants possess the ability to downregulate macrophage activation by suppressing the production of interleukin-12 (IL-12) and nitric oxide. Third, during the stationary phase,iscl−promastigotes were extremely vulnerable to acidic pH but not to other adverse conditions, such as elevated temperature and oxidative/nitrosative stress. In addition, inhibition of phagosomal acidification significantly improvediscl−survival in murine macrophages. Together, these findings indicate that SL degradation byLeishmaniais essential for its adaption to the acidic environment in phagolysosomes but is not required for the suppression of host cell activation. Finally, our studies withiscl−mutant-infected mice suggest that having viable, persistent parasites is not sufficient to provide immunity against virulentLeishmaniachallenge.
Spontaneous Phthiocerol Dimycocerosate-Deficient Variants of Mycobacterium tuberculosis Are Susceptible to Gamma Interferon-Mediated Immunity
Authors: Kirksey Meghan A. , Tischler Anna D. , Siméone Roxane , Hisert Katherine B. , Uplekar Swapna , Guilhot Christophe , McKinney John D. 
Published: May 2011

ABSTRACT

Onset of the adaptive immune response in mice infected with
Mycobacterium tuberculosis
is accompanied by slowing of bacterial replication and establishment of a chronic infection. Stabilization of bacterial numbers during the chronic phase of infection is dependent on the activity of the gamma interferon (IFN-γ)-inducible nitric oxide synthase (NOS2). Previously, we described a differential signature-tagged mutagenesis screen designed to identify
M. tuberculosis
“counterimmune” mechanisms and reported the isolation of three mutants in the H37Rv strain background containing transposon insertions in the
rv0072
,
rv0405
, and
rv2958c
genes. These mutants were impaired for replication and virulence in NOS2
−/−
mice but were growth-proficient and virulent in IFN-γ
−/−
mice, suggesting that the disrupted genes were required for bacterial resistance to an IFN-γ-dependent immune mechanism other than NOS2. Here, we report that the attenuation of these strains is attributable to an underlying transposon-independent deficiency in biosynthesis of phthiocerol dimycocerosate (PDIM), a cell wall lipid that is required for full virulence in mice. We performed whole-genome resequencing of a PDIM-deficient clone and identified a spontaneous point mutation in the putative polyketide synthase PpsD that results in a G44C amino acid substitution. We demonstrate by complementation with the wild-type
ppsD
gene and reversion of the
ppsD
gene to the wild-type sequence that the
ppsD
(G44C) point mutation is responsible for PDIM deficiency, virulence attenuation in NOS2
−/−
and wild-type C57BL/6 mice, and a growth advantage
in vitro
in liquid culture. We conclude that PDIM biosynthesis is required for
M. tuberculosis
resistance to an IFN-γ-mediated immune response that is independent of NOS2.
Genomic and Surface Proteomic Analysis of the Canine Pathogen Staphylococcus pseudintermedius Reveals Proteins That Mediate Adherence to the Extracellular Matrix
Authors: Bannoehr Jeanette , Ben Zakour Nouri L. , Reglinski Mark , Inglis Neil F. , Prabhakaran Sabitha , Fossum Even , Smith David G. , Wilson Gillian J. , Cartwright Robyn A. , Haas Juergen , Hook Magnus , van den Broek Adri H. M. , Thoday Keith L. , Fitzgerald J. Ross 
Published: May 2011

ABSTRACTCell wall-associated (CWA) proteins made by Gram-positive pathogens play a fundamental role in pathogenesis.Staphylococcus pseudintermediusis a major animal pathogen responsible for the canine skin disease bacterial pyoderma. Here, we describe the bioinformatic analysis of the family of 18 predicted CWA proteins encoded in the genome ofS. pseudintermediusstrain ED99 and determine their distribution among a phylogenetically diverse panel ofS. pseudintermediusclinical isolates and closely related species of theStaphylococcus intermediusgroup. In parallel, we employed a proteomic approach to identify proteins presented on the surface of strain ED99in vitro, revealing a total of 60 surface-localized proteins in one or more phases of growth, including 6 of the 18 genome-predicted CWA proteins. Based on these analyses, we selected two CWA proteins (SpsD and SpsL) encoded by all strains examined and investigated their capacity to mediate adherence to extracellular matrix proteins. We discovered that SpsD and SpsL mediated binding of a heterologous host,Lactococcus lactis, to fibrinogen and fibronectin and that SpsD mediated binding to cytokeratin 10, a major constituent of mammalian skin. Of note, the interaction with fibrinogen was host-species dependent, suggestive of a role for SpsD and SpsL in the host tropism ofS. pseudintermedius. Finally, we identified IgG specific for SpsD and SpsL in sera from dogs with bacterial pyoderma, implying that both proteins are expressed during infection. The combined genomic and proteomic approach employed in the current study has revealed novel host-pathogen interactions which represent candidate therapeutic targets for the control of bacterial pyoderma.
Bacillus cereus G9241 Makes Anthrax Toxin and Capsule like Highly Virulent B. anthracis Ames but Behaves like Attenuated Toxigenic Nonencapsulated B. anthracis Sterne in Rabbits and Mice
Authors: Wilson Melissa K. , Vergis James M. , Alem Farhang , Palmer John R. , Keane-Myers Andrea M. , Brahmbhatt Trupti N. , Ventura Christy L. , O'Brien Alison D. 
Published: May 2011

ABSTRACT

Bacillus cereus
G9241 was isolated from a welder with a pulmonary anthrax-like illness. The organism contains two megaplasmids, pBCXO1 and pBC218. These plasmids are analogous to the
Bacillus anthracis
Ames plasmids pXO1 and pXO2 that encode anthrax toxins and capsule, respectively. Here we evaluated the virulence of
B. cereus
G9241 as well as the contributions of pBCXO1 and pBC218 to virulence.
B. cereus
G9241 was avirulent in New Zealand rabbits after subcutaneous inoculation and attenuated 100-fold compared to the published 50% lethal dose (LD
50
) values for
B. anthracis
Ames after aerosol inoculation. A/J and C57BL/6J mice were comparably susceptible to
B. cereus
G9241 by both subcutaneous and intranasal routes of infection. However, the LD
50
s for
B. cereus
G9241 in both mouse strains were markedly higher than those reported for
B. anthracis
Ames and more like those of the toxigenic but nonencapsulated
B. anthracis
Sterne. Furthermore,
B. cereus
G9241 spores could germinate and disseminate after intranasal inoculation into A/J mice, as indicated by the presence of vegetative cells in the spleen and blood of animals 48 h after infection. Lastly,
B. cereus
G9241 derivatives cured of one or both megaplasmids were highly attenuated in A/J mice. We conclude that the presence of the toxin- and capsule-encoding plasmids pBCXO1 and pBC218 in
B. cereus
G9241 alone is insufficient to render the strain as virulent as
B. anthracis
Ames. However, like
B. anthracis
, full virulence of
B. cereus
G9241 for mice requires the presence of both plasmids.
Suppressed Induction of Proinflammatory Cytokines by a Unique Metabolite Produced by Vibrio cholerae O1 El Tor Biotype in Cultured Host Cells
Authors: Bari Wasimul , Song Yoon-Jae , Yoon Sang Sun 
Published: May 2011

ABSTRACTVibrio choleraeO1 has two biotypes, El Tor and Classical, and the latter is now presumed to be extinct in nature. Under carbohydrate-rich growth conditions, El Tor biotype strains produce the neutral fermentation end product 2,3-butanediol (2,3-BD), which prevents accumulation of organic acids from mixed acid fermentation and thus avoids a lethal decrease in the medium pH, while the Classical biotype strains fail to do the same. In this study, we investigated the inhibitory effect of 2,3-BD on the production of two proinflammatory biomarkers, intreleukin-8 (IL-8) and tumor necrosis factor alpha (TNF-α), in human intestinal epithelial HT29 and alveolar epithelial A549 cells. Cell-free culture supernatants of El Tor strain N16961 grown in LB supplemented with 1% glucose induced a negligible amount of IL-8 or TNF-α, while the Classical O395 strain induced much higher levels of these proinflammatory cytokines. On the other hand, three mutant strains constructed from the N16961 strain with defects in the constitutive 2,3-BD pathway were also able to induce high levels of cytokines. When HT29 and A549 cells were treated with bacterial flagella, known proinflammatory cytokine inducers, and chemically synthesized 2,3-BD at various concentrations, a dose-dependent decrease in IL-8 and TNF-α production was observed, demonstrating the suppressive effect of 2,3-BD on the production of proinflammatory cytokines in epithelial cells. Upon cotreatment with extraneous 2,3-BD, elevated levels of IκBα, the inhibitor of the NF-κB pathway, were detected in both HT29 and A549 cells. Furthermore, treatments containing 2,3-BD elicited lower levels of NF-κB-responsive luciferase activity, demonstrating that the reduced cytokine production is likely through the inhibition of the NF-κB pathway. These results reveal a novel and potential role of 2,3-BD as an immune modulator that might have conferred a superior pathogenic potential of the El Tor over the Classical biotype.
Helicobacter pylori AlpA and AlpB Bind Host Laminin and Influence Gastric Inflammation in Gerbils
Authors: Senkovich Olga A. , Yin Jun , Ekshyyan Viktoriya , Conant Carolyn , Traylor James , Adegboyega Patrick , McGee David J. , Rhoads Robert E. , Slepenkov Sergey , Testerman Traci L. 
Published: May 2011

ABSTRACT

Helicobacter pylori
persistently colonizes humans, causing gastritis, ulcers, and gastric cancer. Adherence to the gastric epithelium has been shown to enhance inflammation, yet only a few
H. pylori
adhesins have been paired with targets in host tissue. The
alpAB
locus has been reported to encode adhesins involved in adherence to human gastric tissue. We report that abrogation of
H. pylori
AlpA and AlpB reduces binding of
H. pylori
to laminin while expression of plasmid-borne
alpA
or
alpB
confers laminin-binding ability to
Escherichia coli
. An
H. pylori
strain lacking only AlpB is also deficient in laminin binding. Thus, we conclude that both AlpA and AlpB contribute to
H. pylori
laminin binding. Contrary to expectations, the
H. pylori
SS1 mutant deficient in AlpA and AlpB causes more severe inflammation than the isogenic wild-type strain in gerbils. Identification of laminin as the target of AlpA and AlpB will facilitate future investigations of host-pathogen interactions occurring during
H. pylori
infection.
LOX-1 Deletion Improves Neutrophil Responses, Enhances Bacterial Clearance, and Reduces Lung Injury in a Murine Polymicrobial Sepsis Model
Authors: Wu Zhuang , Sawamura Tatsuya , Kurdowska Anna K. , Ji Hong-Long , Idell Steven , Fu Jian 
Published: May 2011

ABSTRACTInflammatory tissue injury and immunosuppression are the major causes of death in sepsis. Novel therapeutic targets that can prevent excessive inflammation and improve immune responses during sepsis could be critical for treatment of this devastating disease. LOX-1 (lectin-like oxidized low-density lipoprotein receptor-1), a membrane protein expressed in endothelial cells, has been known to mediate vascular inflammation. In the present study, we demonstrated that LOX-1 deletion markedly improved the survival rate in a murine model of polymicrobial sepsis. Wild-type (LOX-1+/+) and LOX-1 knockout (LOX-1−/−) mice were subjected to cecal ligation and puncture (CLP) to induce sepsis. LOX-1 deletion significantly reduced systemic inflammation and inflammatory lung injury during sepsis, together with decreased production of proinflammatory cytokines and reduced lung edema formation. Furthermore, LOX-1 deletion improved host immune responses after the induction of sepsis, as indicated by enhanced bacterial clearance. Interestingly, we were able to demonstrate that LOX-1 is expressed in neutrophils. LOX-1 deletion prevented neutrophil overreaction and increased neutrophil recruitment to infection sites after sepsis induction, contributing at least partly to increased immune responses in LOX-1 knockout mice. Our study results indicate that LOX-1 is an important mediator of inflammation and neutrophil dysfunction in sepsis.
Glycogen Synthase Kinase 3 Activation Is Important for Anthrax Edema Toxin-Induced Dendritic Cell Maturation and Anthrax Toxin Receptor 2 Expression in Macrophages
Authors: Larabee Jason L. , Maldonado-Arocho Francisco J. , Pacheco Sergio , France Bryan , DeGiusti Kevin , Shakir Salika M. , Bradley Kenneth A. , Ballard Jimmy D. 
Published: May 2011

ABSTRACT

Anthrax edema toxin (ET) is one of two binary toxins produced by
Bacillus anthracis
that contributes to the virulence of this pathogen. ET is an adenylate cyclase that generates high levels of cyclic AMP (cAMP), causing alterations in multiple host cell signaling pathways. We previously demonstrated that ET increases cell surface expression of the anthrax toxin receptors (ANTXR) in monocyte-derived cells and promotes dendritic cell (DC) migration toward the lymph node-homing chemokine MIP-3β. In this work, we sought to determine if glycogen synthase kinase 3 (GSK-3) is important for ET-induced modulation of macrophage and DC function. We demonstrate that inhibition of GSK-3 dampens ET-induced maturation and migration processes of monocyte-derived dendritic cells (MDDCs). Additional studies reveal that the ET-induced expression of ANTXR in macrophages was decreased when GSK-3 activity was disrupted with chemical inhibitors or with small interfering RNA (siRNA) targeting GSK-3. Further examination of the ET induction of ANTXR revealed that a dominant negative form of CREB could block the ET induction of ANTXR, suggesting that CREB or a related family member was involved in the upregulation of ANTXR. Because CREB and GSK-3 activity appeared to be important for ET-induced ANTXR expression, the impact of GSK-3 on ET-induced CREB activity was examined in RAW 264.7 cells possessing a CRE-luciferase reporter. As with ANTXR expression, the ET induction of the CRE reporter was decreased by reducing GSK-3 activity. These studies not only provide insight into host pathways targeted by ET but also shed light on interactions between GSK-3 and CREB pathways in host immune cells.
Expression of Anaplasma marginale Ankyrin Repeat-Containing Proteins during Infection of the Mammalian Host and Tick Vector
Authors: Ramabu Solomon S. , Schneider David A. , Brayton Kelly A. , Ueti Massaro W. , Graça Telmo , Futse James E. , Noh Susan M. , Baszler Timothy V. , Palmer Guy H. 
Published: May 2011

ABSTRACT

Transmission of tick-borne pathogens requires transition between distinct host environments with infection and replication in host-specific cell types.
Anaplasma marginale
illustrates this transition: in the mammalian host, the bacterium infects and replicates in mature (nonnucleated) erythrocytes, while in the tick vector, replication occurs in nucleated epithelial cells. We hypothesized that proteins containing ankyrin motifs would be expressed by
A. marginale
only in tick cells and would traffic to the infected host cell nucleus.
A. marginale
encodes three proteins containing ankyrin motifs, an AnkA orthologue (the AM705 protein), AnkB (the AM926 protein), and AnkC (the AM638 protein). All three
A. marginale
Anks were confirmed to be expressed during intracellular infection: AnkA is expressed at significantly higher levels in erythrocytes, AnkB is expressed equally by both infected erythrocytes and tick cells, and AnkC is expressed exclusively in tick cells. There was no evidence of any of the Ank proteins trafficking to the nucleus. Thus, the hypothesis that ankyrin-containing motifs were predictive of cell type expression and nuclear localization was rejected. In contrast, AnkA orthologues in the closely related
A. phagocytophilum
and
Ehrlichia chaffeensis
have been shown to localize to the host cell nucleus. This difference, together with the lack of a nuclear localization signal in any of the AnkA orthologues, suggests that trafficking may be mediated by a separate transporter rather than by endogenous signals. Selection for divergence in Ank function among
Anaplasma
and
Ehrlichia
spp. is supported by both locus and allelic analyses of genes encoding orthologous proteins and their ankyrin motif compositions.
Klebsiella pneumoniae Yersiniabactin Promotes Respiratory Tract Infection through Evasion of Lipocalin 2
Authors: Bachman Michael A. , Oyler Jennifer E. , Burns Samuel H. , Caza Mélissa , Lépine François , Dozois Charles M. , Weiser Jeffrey N. 
Published: May 2011

ABSTRACT

Klebsiella pneumoniae
is a pathogen of increasing concern because of multidrug resistance, especially due to
K. pneumoniae
carbapenemases (KPCs).
K. pneumoniae
must 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 whether
K. pneumoniae
must 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 of
K. pneumoniae
isolates 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). In
ex vivo
growth 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 in
Lcn2
−/−
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-producing
K. pneumoniae
isolates and promotes respiratory tract infections through evasion of Lcn2.
The Borrelia burgdorferi Integrin Ligand P66 Affects Gene Expression by Human Cells in Culture
Authors: LaFrance Michelle E. , Pierce Jessica V. , Antonara Syliani , Coburn Jenifer 
Published: May 2011

ABSTRACTBorrelia burgdorferi, an agent of Lyme disease, establishes persistent infection in immunocompetent animals and humans. Although the infection in humans can be cleared by antibiotic therapy, persistence in reservoir animals is necessary for the maintenance of the bacterium in the natural reservoir host⇔tick vector infectious cycle.B. burgdorferibinds to β1- and β3-chain integrins, and the P66 outer membrane protein is responsible for at least some of the integrin binding activity of the spirochete. Because integrins are transmembrane, bidirectional signaling molecules, integrin binding may alter the nature of the host response to the bacteria. We used isogenicB. burgdorferip66+andΔp66strains to analyze the responses of cultured human cells to P66-integrin interaction during infection. Microarray results suggest that the response differs according to the cell type, infection time, and experimental conditions. Clusters of genes in functionally related categories that showed significant changes included proteins involved in cell-extracellular matrix interactions, actin dynamics, stress response, and immune responses. Integrin binding by P66 may therefore helpB. burgdorferiestablish infection by facilitating tissue invasion and modulating the activation of the immune system to other components of the bacteria, e.g., lipoproteins. These results provide insight into howB. burgdorferiis able to establish infection in immunocompetent hosts.