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Search Results: 1 - 10 of 464973 matches for " Bruce A. Vallance "
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A Novel Secretion Pathway of Salmonella enterica Acts as an Antivirulence Modulator during Salmonellosis
Ohad Gal-Mor,Deanna L. Gibson,Dan Baluta,Bruce A. Vallance,B. Brett Finlay
PLOS Pathogens , 2008, DOI: 10.1371/journal.ppat.1000036
Abstract: Salmonella spp. are Gram-negative enteropathogenic bacteria that infect a variety of vertebrate hosts. Like any other living organism, protein secretion is a fundamental process essential for various aspects of Salmonella biology. Herein we report the identification and characterization of a horizontally acquired, autonomous and previously unreported secretion pathway. In Salmonella enterica serovar Typhimurium, this novel secretion pathway is encoded by STM1669 and STM1668, designated zirT and zirS, respectively. We show that ZirT is localized to the bacterial outer membrane, expected to adopt a compact β-barrel conformation, and functions as a translocator for ZirS. ZirS is an exoprotein, which is secreted into the extracellular environment in a ZirT-dependent manner. The ZirTS secretion pathway was found to share several important features with two-partner secretion (TPS) systems and members of the intimin/invasin family of adhesions. We show that zirTS expression is affected by zinc; and that in vivo, induction of zirT occurs distinctively in Salmonella colonizing the small intestine, but not in systemic sites. Additionally, strong expression of zirT takes place in Salmonella shed in fecal pellets during acute and persistent infections of mice. Inactivation of ZirTS results in a hypervirulence phenotype of Salmonella during oral infection of mice. Cumulatively, these results indicate that the ZirTS pathway plays a unique role as an antivirulence modulator during systemic disease and is involved in fine-tuning a host–pathogen balance during salmonellosis.
Salmonella Pathogenicity Island 2 Is Expressed Prior to Penetrating the Intestine
Nat F Brown equal contributor,Bruce A Vallance equal contributor,Brian K Coombes,Yanet Valdez,Bryan A Coburn,B. Brett Finlay
PLOS Pathogens , 2005, DOI: 10.1371/journal.ppat.0010032
Abstract: Salmonella enterica serovar Typhimurium is a facultative intracellular pathogen that causes disease in mice that resembles human typhoid. Typhoid pathogenesis consists of distinct phases in the intestine and a subsequent systemic phase in which bacteria replicate in macrophages of the liver and spleen. The type III secretion system encoded by Salmonella pathogenicity island 2 (SPI-2) is a major virulence factor contributing to the systemic phase of typhoid pathogenesis. Understanding how pathogens regulate virulence mechanisms in response to the environment, including different host tissues, is key to our understanding of pathogenesis. A recombinase-based in vivo expression technology system was developed to assess SPI-2 expression during murine typhoid. SPI-2 expression was detectable at very early times in bacteria that were resident in the lumen of the ileum and was independent of active bacterial invasion of the epithelium. We also provide direct evidence for the regulation of SPI-2 by the Salmonella transcription factors ompR and ssrB in vivo. Together these results demonstrate that SPI-2 expression precedes penetration of the intestinal epithelium. This induction of expression precedes any documented SPI-2-dependent phases of typhoid and may be involved in preparing Salmonella to successfully resist the antimicrobial environment encountered within macrophages.
Epithelial p38α Controls Immune Cell Recruitment in the Colonic Mucosa
Young Jun Kang equal contributor,Motoyuki Otsuka equal contributor,Arjen van den Berg,Lixin Hong,Zhe Huang,Xiurong Wu,Duan-Wu Zhang,Bruce A. Vallance,Peter S. Tobias,Jiahuai Han
PLOS Pathogens , 2010, DOI: 10.1371/journal.ppat.1000934
Abstract: Intestinal epithelial cells (IECs) compose the first barrier against microorganisms in the gastrointestinal tract. Although the NF-κB pathway in IECs was recently shown to be essential for epithelial integrity and intestinal immune homeostasis, the roles of other inflammatory signaling pathways in immune responses in IECs are still largely unknown. Here we show that p38α in IECs is critical for chemokine expression, subsequent immune cell recruitment into the intestinal mucosa, and clearance of the infected pathogen. Mice with p38α deletion in IECs suffer from a sustained bacterial burden after inoculation with Citrobacter rodentium. These animals are normal in epithelial integrity and immune cell function, but fail to recruit CD4+ T cells into colonic mucosal lesions. The expression of chemokines in IECs is impaired, which appears to be responsible for the impaired T cell recruitment. Thus, p38α in IECs contributes to the host immune responses against enteric bacteria by the recruitment of immune cells.
Muc2 Protects against Lethal Infectious Colitis by Disassociating Pathogenic and Commensal Bacteria from the Colonic Mucosa
Kirk S. B. Bergstrom,Vanessa Kissoon-Singh,Deanna L. Gibson,Caixia Ma,Marinieve Montero,Ho Pan Sham,Natasha Ryz,Tina Huang,Anna Velcich,B. Brett Finlay,Kris Chadee ,Bruce A. Vallance
PLOS Pathogens , 2010, DOI: 10.1371/journal.ppat.1000902
Abstract: Despite recent advances in our understanding of the pathogenesis of attaching and effacing (A/E) Escherichia coli infections, the mechanisms by which the host defends against these microbes are unclear. The goal of this study was to determine the role of goblet cell-derived Muc2, the major intestinal secretory mucin and primary component of the mucus layer, in host protection against A/E pathogens. To assess the role of Muc2 during A/E bacterial infections, we inoculated Muc2 deficient (Muc2?/?) mice with Citrobacter rodentium, a murine A/E pathogen related to diarrheagenic A/E E. coli. Unlike wildtype (WT) mice, infected Muc2?/? mice exhibited rapid weight loss and suffered up to 90% mortality. Stool plating demonstrated 10–100 fold greater C. rodentium burdens in Muc2?/? vs. WT mice, most of which were found to be loosely adherent to the colonic mucosa. Histology of Muc2?/? mice revealed ulceration in the colon amid focal bacterial microcolonies. Metabolic labeling of secreted mucins in the large intestine demonstrated that mucin secretion was markedly increased in WT mice during infection compared to uninfected controls, suggesting that the host uses increased mucin release to flush pathogens from the mucosal surface. Muc2 also impacted host-commensal interactions during infection, as FISH analysis revealed C. rodentium microcolonies contained numerous commensal microbes, which was not observed in WT mice. Orally administered FITC-Dextran and FISH staining showed significantly worsened intestinal barrier disruption in Muc2?/? vs. WT mice, with overt pathogen and commensal translocation into the Muc2?/? colonic mucosa. Interestingly, commensal depletion enhanced C. rodentium colonization of Muc2?/? mice, although colonic pathology was not significantly altered. In conclusion, Muc2 production is critical for host protection during A/E bacterial infections, by limiting overall pathogen and commensal numbers associated with the colonic mucosal surface. Such actions limit tissue damage and translocation of pathogenic and commensal bacteria across the epithelium.
SIGIRR, a Negative Regulator of TLR/IL-1R Signalling Promotes Microbiota Dependent Resistance to Colonization by Enteric Bacterial Pathogens
Ho Pan Sham,Emily Yi Shan Yu,Muhammet F. Gulen,Ganive Bhinder,Martin Stahl,Justin M. Chan,Lara Brewster,Vijay Morampudi,Deanna L. Gibson,Michael R. Hughes,Kelly M. McNagny,Xiaoxia Li ,Bruce A. Vallance
PLOS Pathogens , 2013, DOI: 10.1371/journal.ppat.1003539
Abstract: Enteric bacterial pathogens such as enterohemorrhagic E. coli (EHEC) and Salmonella Typhimurium target the intestinal epithelial cells (IEC) lining the mammalian gastrointestinal tract. Despite expressing innate Toll-like receptors (TLRs), IEC are innately hypo-responsive to most bacterial products. This is thought to prevent maladaptive inflammatory responses against commensal bacteria, but it also limits antimicrobial responses by IEC to invading bacterial pathogens, potentially increasing host susceptibility to infection. One reason for the innate hypo-responsiveness of IEC is their expression of Single Ig IL-1 Related Receptor (SIGIRR), a negative regulator of interleukin (IL)-1 and TLR signaling. To address whether SIGIRR expression and the innate hypo-responsiveness of IEC impacts on enteric host defense, Sigirr deficient (?/?) mice were infected with the EHEC related pathogen Citrobacter rodentium. Sigirr ?/? mice responded with accelerated IEC proliferation and strong pro-inflammatory and antimicrobial responses but surprisingly, Sigirr ?/? mice proved dramatically more susceptible to infection than wildtype mice. Through haematopoietic transplantation studies, it was determined that SIGIRR expression by non-haematopoietic cells (putative IEC) regulated these responses. Moreover, the exaggerated responses were found to be primarily dependent on IL-1R signaling. Whilst exploring the basis for their susceptibility, Sigirr ?/? mice were found to be unusually susceptible to intestinal Salmonella Typhimurium colonization, developing enterocolitis without the typical requirement for antibiotic based removal of competing commensal microbes. Strikingly, the exaggerated antimicrobial responses seen in Sigirr ?/? mice were found to cause a rapid and dramatic loss of commensal microbes from the infected intestine. This depletion appears to reduce the ability of the microbiota to compete for space and nutrients (colonization resistance) with the invading pathogens, leaving the intestine highly susceptible to pathogen colonization. Thus, SIGIRR expression by IEC reflects a strategy that sacrifices maximal innate responsiveness by IEC in order to promote commensal microbe based colonization resistance against bacterial pathogens.
A Novel Mouse Model of Campylobacter jejuni Gastroenteritis Reveals Key Pro-inflammatory and Tissue Protective Roles for Toll-like Receptor Signaling during Infection
Martin Stahl,Jenna Ries equal contributor,Jenny Vermeulen equal contributor,Hong Yang,Ho Pan Sham,Shauna M. Crowley,Yuliya Badayeva,Stuart E. Turvey,Erin C. Gaynor ?,Xiaoxia Li ?,Bruce A. Vallance
PLOS Pathogens , 2014, DOI: doi/10.1371/journal.ppat.1004264
Abstract: Campylobacter jejuni is a major source of foodborne illness in the developed world, and a common cause of clinical gastroenteritis. Exactly how C. jejuni colonizes its host's intestines and causes disease is poorly understood. Although it causes severe diarrhea and gastroenteritis in humans, C. jejuni typically dwells as a commensal microbe within the intestines of most animals, including birds, where its colonization is asymptomatic. Pretreatment of C57BL/6 mice with the antibiotic vancomycin facilitated intestinal C. jejuni colonization, albeit with minimal pathology. In contrast, vancomycin pretreatment of mice deficient in SIGIRR (Sigirr?/?), a negative regulator of MyD88-dependent signaling led to heavy and widespread C. jejuni colonization, accompanied by severe gastroenteritis involving strongly elevated transcription of Th1/Th17 cytokines. C. jejuni heavily colonized the cecal and colonic crypts of Sigirr?/? mice, adhering to, as well as invading intestinal epithelial cells. This infectivity was dependent on established C. jejuni pathogenicity factors, capsular polysaccharides (kpsM) and motility/flagella (flaA). We also explored the basis for the inflammatory response elicited by C. jejuni in Sigirr?/? mice, focusing on the roles played by Toll-like receptors (TLR) 2 and 4, as these innate receptors were strongly stimulated by C. jejuni. Despite heavy colonization, Tlr4?/?/Sigirr?/? mice were largely unresponsive to infection by C. jejuni, whereas Tlr2?/?/Sigirr?/? mice developed exaggerated inflammation and pathology. This indicates that TLR4 signaling underlies the majority of the enteritis seen in this model, whereas TLR2 signaling had a protective role, acting to promote mucosal integrity. Furthermore, we found that loss of the C. jejuni capsule led to increased TLR4 activation and exaggerated inflammation and gastroenteritis. Together, these results validate the use of Sigirr?/? mice as an exciting and relevant animal model for studying the pathogenesis and innate immune responses to C. jejuni.
Foreign Bodies: Aspirated or Ingested? A Report of Two Unusual Cases
Aliasghar Arabi Mianroodi,Yeganeh Teimouri,Neil A.Vallance
Iranian Journal of Otorhinolaryngology , 2011,
Abstract: Introduction: The diagnosis of foreign bodies in the upper aerodigestive tract is usually straightforward but sometimes it can be delayed or the location of esophageal and upper airway foreign bodies can be mistakenly interchanged. Case Report: We present two interesting cases that caused diagnostic challenges which could have led to serious complications if a greater delay in diagnosis had occurred. Conclusion: In order to diagnose upper aerodigestive tract foreign bodies without delay, a careful history and physical examination with proper X-rays are helpful.
On I(5577 ) and I (7620 ) auroral emissions and atomic oxygen densities
R. L. Gattinger,E. J. Llewellyn,A. Vallance Jones
Annales Geophysicae (ANGEO) , 2003,
Abstract: A model of auroral electron deposition processes has been developed using Monte Carlo techniques to simulate electron transport and energy loss. The computed differential electron flux and pitch angle were compared with in situ auroral observations to provide a check on the accuracy of the model. As part of the energy loss process, a tally was kept of electronic excitation and ionization of the important atomic and molecular states. The optical emission rates from these excited states were computed and compared with auroral observations of η(3914 ), η(5577 ), η(7620 ) and η(N2VK). In particular, the roles played by energy transfer from N2(A3Σ+u) and by other processes in the excitation of O(1S) and O2(b1Σ+g) were investigated in detail. It is concluded that the N2(A3Σ+u) mechanism is dominant for the production of OI(5577 ) in the peak emission region of normal aurora, although the production efficiency is much smaller than the measured laboratory value; above 150 km electron impact on atomic oxygen is dominant. Atomic oxygen densities in the range of 0.75±0.25 MSIS-86 [O] were derived from the optical comparisons for auroral latitudes in mid-winter for various levels of solar and magnetic activity.
On the variability of I(7620 )/I(5577 ) in low altitude aurora
E. J. Llewellyn,R. L. Gattinger,A. Vallance Jones
Annales Geophysicae (ANGEO) , 2003,
Abstract: An auroral electron excitation model, combined with simple equilibrium neutral and ion chemistry models, is used to investigate the optical emission processes and height profiles of I(5577 ) and I(7620 ) in the 90 to 100 km altitude region. It is shown that the apparent discrepancies between ground-based and rocket-borne auroral observations of the I(7620 )/I(5577 ) ratio are due to the extreme height variation of this intensity ratio in the 90 to 100 km region. Key words. Atmospheric composition and structure (airglow and aurora)
An information and communications technology (ICT)-enabled method for collecting and collating information about pre-service teachers' pedagogical beliefs regarding the integration of ICT
Michael Vallance
Research in Learning Technology , 2007, DOI: 10.3402/rlt.v15i1.10912
Abstract: This paper describes a method that utilized technology to collect and collate quantitative and qualitative data about pre-service teachers' use of networked technologies during a 12-week undergraduate course, and the impact of this use on their pedagogical beliefs regarding the integration of information and communications technology (ICT). The technologies used captured and analysed students' spoken and written communication while engaging in four synchronous online tasks, and also collected evaluation data from online interviews, surveys and diaries. The richness of data afforded by this ICT-enabled method enabled the research to produce a rich narrative of how the students used the technology and provided evidence of a change in pre-service teachers' pedagogical beliefs during the course.
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