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Search Results: 1 - 10 of 146193 matches for " Brian K Coombes "
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A Fresh Look at the Type III Secretion System: Two-Step Model of Effector Translocation in Pathogenic Bacteria
Brian K. Coombes
Frontiers in Microbiology , 2011, DOI: 10.3389/fmicb.2011.00113
The Evolution of Virulence in Non-O157 Shiga Toxin-Producing Escherichia Coli
Brian K. Coombes
Frontiers in Microbiology , 2011, DOI: 10.3389/fmicb.2011.00090
Abstract: Shiga toxin-producing Escherichia coli (STEC) are zoonotic foodborne and waterborne pathogens that are a serious public health concern because they cause outbreaks and the potentially fatal hemolytic uremic syndrome (HUS). The most common STEC serotype associated with human disease is O157:H7, but there is a growing recognition of over 100 non-O157 serotypes that also may result in human illness. Some of these non-O157 STEC strains cause outbreaks and severe disease such as HUS and hemorrhagic colitis, whereas others are associated with only mild diarrhea or with no human disease at all. The relative scarceness of whole genome sequence data for non-O157 STEC has limited the scientific discovery into the genetic basis of these differences in virulence. Uncovering the scope of genetic diversity and phylogeny of the non-O157 STEC through targeting sequencing of clinically relevant isolates will offer new biological insight to the pathogenic behavior of these emerging pathogens. These approaches would also enable molecular risk assessment strategies to rapidly identify and respond to emerging non-O157 STEC that pose a serious public health risk to humans.
Transcriptional Priming of Salmonella Pathogenicity Island-2 Precedes Cellular Invasion
Suzanne E. Osborne, Brian K. Coombes
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0021648
Abstract: Invasive salmonellosis caused by Salmonella enterica involves an enteric stage of infection where the bacteria colonize mucosal epithelial cells, followed by systemic infection with intracellular replication in immune cells. The type III secretion system encoded in Salmonella Pathogenicity Island (SPI)-2 is essential for intracellular replication and the regulators governing high-level expression of SPI-2 genes within the macrophage phagosome and in inducing media thought to mimic this environment have been well characterized. However, low-level expression of SPI-2 genes is detectable in media thought to mimic the extracellular environment suggesting that additional regulatory pathways are involved in SPI-2 gene expression prior to cellular invasion. The regulators involved in this activity are not known and the extracellular transcriptional activity of the entire SPI-2 island in vivo has not been studied. We show that low-level, SsrB-independent promoter activity for the ssrA-ssrB two-component regulatory system and the ssaG structural operon encoded in SPI-2 is dependent on transcriptional input by OmpR and Fis under non-inducing conditions. Monitoring the activity of all SPI-2 promoters in real-time following oral infection of mice revealed invasion-independent transcriptional activity of the SPI2 T3SS in the lumen of the gut, which we suggest is a priming activity with functional relevance for the subsequent intracellular host-pathogen interaction.
RpoE fine tunes expression of a subset of SsrB-regulated virulence factors in Salmonella enterica serovar Typhimurium
Suzanne E Osborne, Brian K Coombes
BMC Microbiology , 2009, DOI: 10.1186/1471-2180-9-45
Abstract: In this study we demonstrate that RpoE is involved in fine-tuning the expression of a subset of SsrB-regulated genes found in the Salmonella pathogenicity island-2 (SPI-2) genetic locus that encodes a horizontally acquired type III secretion system, and unlinked genes integrated into this regulon that are required for virulence in host animals.These data point to a potential connection between the virulence phenotype of strains lacking ssrB and rpoE, and highlight new transcriptional regulation that might be essential for appropriate temporal and spatial control of the virulence-associated type III secretion system during host infection.Salmonella enterica are enteric pathogens that acquired a type III secretion system (T3SS) through horizontal gene transfer of a genomic island termed Salmonella Pathogenicity Island 2 (SPI-2) [1,2]. The SPI-2-encoded T3SS and its translocated effectors modify the intracellular host niche for Salmonella replication [3-5]. SPI-2 also has genes, ssrA and ssrB, which code for SsrAB, a two-component regulatory system needed for expression of the T3SS [6,7]. SsrB regulates the expression of SPI-2 encoded substrate effectors including ssaB, as well as several integrated virulence effectors such as sseL [8] and srfN [9] that are encoded elsewhere on the chromosome but that have integrated into the SsrB regulon. Mutants lacking ssrAB are unable to survive within macrophages and are avirulent in mice [1].Alternative sigma factors coordinate gene expression in response to environmental cues sensed by the bacterium. Sigma factors have a specific recognition motif at the -35 and -10 positions and function to concentrate RNA polymerase at a subset of promoters [10]. One alternative sigma factor, RpoE (σE) responds to envelope stress at the cell surface. Release of σE from its inner membrane anchored anti-sigma factor, RseA, leads to induction of genes required to maintain cell envelope integrity [11]. SsrB-regulated translocated effectors protect
The non-motile phenotype of Salmonella hha ydgT mutants is mediated through PefI-SrgD
Lauren E Wallar, Andrew M Bysice, Brian K Coombes
BMC Microbiology , 2011, DOI: 10.1186/1471-2180-11-141
Abstract: In this study we show that the non-motile phenotype of hha ydgT mutants is due to decreased levels of the master transcriptional regulator FlhD4C2 resulting in down-regulation of class II/III and class III flagellar promoters and lack of surface flagella on these cells. The horizontally acquired pefI-srgD region was found to be partially responsible for this phenotype since deletion of pefI-srgD in a hha ydgT deletion background resulted in transient restoration of class II/III and III transcription, expression of surface flagella, and motility in the quadruple mutant.These data extend our current understanding of the mechanisms through which Hha and YdgT regulate flagellar biosynthesis and further describe how S. Typhimurium has integrated horizontal gene acquisitions into ancestral regulatory networks.The pathogenic nature of Salmonella enterica has been shaped by the horizontal acquisition of virulence determinants [1,2]. In Salmonella enterica serovar Typhimurium (S. Typhimurium), many virulence genes are organized in mobile elements such as pathogenicity islands, prophages, and the Salmonella virulence plasmid [3,4]. The increased pathogenic capacity conferred by such genes is dependent on their integration into ancestral regulatory networks of the cell, which can be accomplished by regulatory evolution following horizontal gene transfer [5].The Hha/YmoA family of small nucleoid-associated proteins in Enterobacteriaceae [6] can participate in fine-tuning virulence gene expression in response to environmental cues [6,7]. For example, YmoA regulates expression of Yop proteins, YadA adhesin, Yst enterotoxin and invasin in Yersinia enterocolitica [7-9]. Hha negatively regulates the α-hemolysin genes hlyCABD in Escherichia coli [10], hilA encoded within Salmonella pathogenicity island 1 (SPI-1) in S. Typhimurium [11] and the locus of enterocyte effacement in enterohemorrhagic E. coli [12]. A third member, YdgT, similarly represses hlyCABD in E. coli [13]. We and oth
Crossing the Line: Selection and Evolution of Virulence Traits
Nat F Brown equal contributor,Mark E Wickham equal contributor,Brian K Coombes,B. Brett Finlay
PLOS Pathogens , 2006, DOI: 10.1371/journal.ppat.0020042
Abstract: The evolution of pathogens presents a paradox. Pathogenic species are often absolutely dependent on their host species for their propagation through evolutionary time, yet the pathogenic lifestyle requires that the host be damaged during this dependence. It is clear that pathogenic strategies are successful in evolutionary terms because a diverse array of pathogens exists in nature. Pathogens also evolve using a broad range of molecular mechanisms to acquire and modulate existing virulence traits in order to achieve this success. Detailing the benefit of enhanced selection derived through virulence and understanding the mechanisms through which virulence evolves are important to understanding the natural world and both have implications for human health.
FimH Adhesin of Type 1 Fimbriae Is a Potent Inducer of Innate Antimicrobial Responses Which Requires TLR4 and Type 1 Interferon Signalling
Ali A. Ashkar ,Karen L. Mossman,Brian K. Coombes,Carlton L. Gyles,Randy Mackenzie
PLOS Pathogens , 2008, DOI: 10.1371/journal.ppat.1000233
Abstract: Components of bacteria have been shown to induce innate antiviral immunity via Toll-like receptors (TLRs). We have recently shown that FimH, the adhesin portion of type 1 fimbria, can induce the innate immune system via TLR4. Here we report that FimH induces potent in vitro and in vivo innate antimicrobial responses. FimH induced an innate antiviral state in murine macrophage and primary MEFs which was correlated with IFN-β production. Moreover, FimH induced the innate antiviral responses in cells from wild type, but not from MyD88?/?, Trif?/?, IFN?α/βR?/? or IRF3?/? mice. Vaginal delivery of FimH, but not LPS, completely protected wild type, but not MyD88?/?, IFN-α/βR?/?, IRF3?/? or TLR4?/? mice from subsequent genital HSV-2 challenge. The FimH-induced innate antiviral immunity correlated with the production of IFN-β, but not IFN-α or IFN-γ. To examine whether FimH plays a role in innate immune induction in the context of a natural infection, the innate immune responses to wild type uropathogenic E. coli (UPEC) and a FimH null mutant were examined in the urinary tract of C57Bl/6 (B6) mice and TLR4-deficient mice. While UPEC expressing FimH induced a robust polymorphonuclear response in B6, but not TLR4?/? mice, mutant bacteria lacking FimH did not. In addition, the presence of TLR4 was essential for innate control of and protection against UPEC. Our results demonstrate that FimH is a potent inducer of innate antimicrobial responses and signals differently, from that of LPS, via TLR4 at mucosal surfaces. Our studies suggest that FimH can potentially be used as an innate microbicide against mucosal pathogens.
Oral infection of mice with Salmonella enterica serovar Typhimurium causes meningitis and infection of the brain
Mark E Wickham, Nat F Brown, John Provias, B Brett Finlay, Brian K Coombes
BMC Infectious Diseases , 2007, DOI: 10.1186/1471-2334-7-65
Abstract: Five mouse lines including C57BL/6, Balb/c, 129S6-Slc11a1tm1Mcg, 129S1/SvImJ, B6.129-Inpp5dtm1Rkh were used in the murine typhoid model to examine the dissemination of systemic Salmonella enterica serovar Typhimurium following oral infection.We report data on spontaneous meningitis and brain infection following oral infection of mice with Salmonella enterica serovar Typhimurium.This model may provide a system in which dissemination of bacteria through the central nervous system and the influence of host and bacterial genetics can be queried.Salmonella species are Gram-negative, facultative intracellular bacteria that are distributed globally. Two recognized species of Salmonella include S. enterica and S. bongori, with S. enterica serovars Typhimurium, Typhi and Enteriditis causing the vast majority of human infections worldwide. Humans are infected with S. enterica though contaminated food and water and present with a range of acute symptoms including gastroenteritis, fever, and headache. Although systemic infections with S. Typhi are uncommon in developed countries, typhoid remains a significant public health problem in the developing world [1]. Infections with non-typhoidal strains of Salmonella are a global burden, with an estimated 1.4 million cases in the United States alone [2].Salmonella meningitis is an uncommon complication of salmonellosis, occurring more frequently in neonates and infants [3,4], although adult cases are reported. While considered rare in the developed world, Salmonella is a common cause of enterobacterial meningitis in Africa, Brazil and Thailand [4,5]. Cases in adults of Salmonella infection report colonization of the cerebrospinal fluid, fatal brain abscesses caused by intracranial colonization of S. enterica serotype Typhimurium [6], adult Salmonella meningitis [7] and CSF pleocytosis [7]. Mortality rates are typically high, especially in infants where rates have been 60% [8]. Other major issues concerning Salmonella meningitis is a h
A novel inhibitor of Chlamydophila pneumoniae protein kinase D (PknD) inhibits phosphorylation of CdsD and suppresses bacterial replication
Dustin L Johnson, Chris B Stone, David C Bulir, Brian K Coombes, James B Mahony
BMC Microbiology , 2009, DOI: 10.1186/1471-2180-9-218
Abstract: Using an in vitro kinase assay we screened 80 known eukaryotic protein kinase inhibitors for activity against PknD and identified a 3'-pyridyl oxindole compound that inhibited PknD autophosphorylation and phosphorylation of CdsD. The PknD inhibitor significantly retarded the growth rate of C. pneumoniae as evidenced by the presence of very small inclusions with a reduced number of bacteria as seen by electron microscopy. These inclusions contained the normal replicative forms including elementary bodies (EB), intermediate bodies (IB) and reticulate bodies (RB), but lacked persistent bodies (PB), indicating that induction of persistence was not the cause of reduced chlamydial growth. Blind passage of C. pneumoniae grown in the presence of this PknD inhibitor for 72 or 84 hr failed to produce inclusions, suggesting this compound blocks an essential step in the production of infectious chlamydial EB. The compound was not toxic to HeLa cells, did not block activation of the MEK/ERK pathway required for chlamydial invasion and did not block intracellular replication of either Chlamydia trachomatis serovar D or Salmonella enterica sv. Typhimurium suggesting that the inhibitory effect of the compound is specific for C. pneumoniae.We have identified a 3'-pyridyl oxindole compound that inhibits the in vitro kinase activity of C. pneumoniae PknD and inhibits the growth and production of infectious C. pneumoniae progeny in HeLa cells. Together, these results suggest that PknD may play a key role in the developmental cycle of C. pneumoniae.Chlamydophila pneumoniae is an important human respiratory pathogen that causes laryngitis, pharyngitis, bronchitis and community acquired pneumonia [1] and has been associated with exacerbation of asthma [2,3], atherosclerosis [4-6], arthritis [2,7], Alzheimer's disease [8,9] and Multiple Sclerosis [10-13]. The ability of C. pneumoniae to remain viable within lung macrophages [14-16] provides a mechanism for dissemination of Chlamydia to oth
Crossing the line: selection and evolution of virulence traits.
Brown Nat F,Wickham Mark E,Coombes Brian K,Finlay B Brett
PLOS Pathogens , 2006,
Abstract: The evolution of pathogens presents a paradox. Pathogenic species are often absolutely dependent on their host species for their propagation through evolutionary time, yet the pathogenic lifestyle requires that the host be damaged during this dependence. It is clear that pathogenic strategies are successful in evolutionary terms because a diverse array of pathogens exists in nature. Pathogens also evolve using a broad range of molecular mechanisms to acquire and modulate existing virulence traits in order to achieve this success. Detailing the benefit of enhanced selection derived through virulence and understanding the mechanisms through which virulence evolves are important to understanding the natural world and both have implications for human health.
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