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Search Results: 1 - 10 of 145375 matches for " B Brett Finlay "
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Breaking the Stereotype: Virulence Factor–Mediated Protection of Host Cells in Bacterial Pathogenesis
Stephanie R. Shames,B. Brett Finlay
PLOS Pathogens , 2010, DOI: 10.1371/journal.ppat.1001057
Abstract:
Should the Human Microbiome Be Considered When Developing Vaccines?
Rosana B. R. Ferreira,L. Caetano M. Antunes,B. Brett Finlay
PLOS Pathogens , 2010, DOI: 10.1371/journal.ppat.1001190
Abstract:
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.
Altering Host Resistance to Infections through Microbial Transplantation
Benjamin P. Willing, Anjalee Vacharaksa, Matthew Croxen, Teerawat Thanachayanont, B. Brett Finlay
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0026988
Abstract: Host resistance to bacterial infections is thought to be dictated by host genetic factors. Infections by the natural murine enteric pathogen Citrobacter rodentium (used as a model of human enteropathogenic and enterohaemorrhagic E. coli infections) vary between mice strains, from mild self-resolving colonization in NIH Swiss mice to lethality in C3H/HeJ mice. However, no clear genetic component had been shown to be responsible for the differences observed with C. rodentium infections. Because the intestinal microbiota is important in regulating resistance to infection, and microbial composition is dependent on host genotype, it was tested whether variations in microbial composition between mouse strains contributed to differences in “host” susceptibility by transferring the microbiota of resistant mice to lethally susceptible mice prior to infection. Successful transfer of the microbiota from resistant to susceptible mice resulted in delayed pathogen colonization and mortality. Delayed mortality was associated with increased IL-22 mediated innate defense including antimicrobial peptides Reg3γ and Reg3β, and immunono-neutralization of IL-22 abrogated the beneficial effect of microbiota transfer. Conversely, depletion of the native microbiota in resistant mice by antibiotics and transfer of the susceptible mouse microbiota resulted in reduced innate defenses and greater pathology upon infection. This work demonstrates the importance of the microbiota and how it regulates mucosal immunity, providing an important factor in susceptibility to enteric infection. Transfer of resistance through microbial transplantation (bacteriotherapy) provides additional mechanisms to alter “host” resistance, and a novel means to alter enteric infection and to study host-pathogen interactions.
The Salmonella enterica PhoP Directly Activates the Horizontally Acquired SPI-2 Gene sseL and Is Functionally Different from a S. bongori Ortholog
Ohad Gal-Mor,Dana Elhadad,Wanyin Deng,Galia Rahav,Brett B. Finlay
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0020024
Abstract: To establish a successful infection within the host, a pathogen must closely regulate multiple virulence traits to ensure their accurate temporal and spatial expression. As a highly adapted intracellular pathogen, Salmonella enterica has acquired during its evolution various virulence genes via numerous lateral transfer events, including the acquisition of the Salmonella Pathogenicity Island 2 (SPI-2) and its associated effectors. Beneficial use of horizontally acquired genes requires that their expression is effectively coordinated with the already existing virulence programs and the regulatory set-up in the bacterium. As an example for such a mechanism, we show here that the ancestral PhoPQ system of Salmonella enterica is able to regulate directly the SPI-2 effector gene sseL (encoding a secreted deubiquitinase) in an SsrB-independent manner and that PhoP plays a part in a feed-forward regulatory loop, which fine-tunes the cellular level of SseL. Additionally, we demonstrate the presence of conserved cis regulatory elements in the promoter region of sseL and show direct binding of purified PhoP to this region. Interestingly, in contrast to the S. enterica PhoP, an ortholog regulator from a S. bongori SARC 12 strain was found to be impaired in promoting transcription of sseL and other genes from the PhoP regulon. These findings have led to the identification of a previously uncharacterized residue in the DNA-binding domain of PhoP, which is required for the transcriptional activation of PhoP regulated genes in Salmonella spp. Collectively our data demonstrate an interesting interface between the acquired SsrB regulon and the ancestral PhoPQ regulatory circuit, provide novel insights into the function of PhoP, and highlight a mechanism of regulatory integration of horizontally acquired genes into the virulence network of Salmonella enterica.
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.
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
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.
Evidence of a Large Novel Gene Pool Associated with Prokaryotic Genomic Islands
William W. L Hsiao,Korine Ung,Dana Aeschliman,Jenny Bryan,B. Brett Finlay,Fiona S. L Brinkman
PLOS Genetics , 2005, DOI: 10.1371/journal.pgen.0010062
Abstract: Microbial genes that are “novel” (no detectable homologs in other species) have become of increasing interest as environmental sampling suggests that there are many more such novel genes in yet-to-be-cultured microorganisms. By analyzing known microbial genomic islands and prophages, we developed criteria for systematic identification of putative genomic islands (clusters of genes of probable horizontal origin in a prokaryotic genome) in 63 prokaryotic genomes, and then characterized the distribution of novel genes and other features. All but a few of the genomes examined contained significantly higher proportions of novel genes in their predicted genomic islands compared with the rest of their genome (Paired t test = 4.43E-14 to 1.27E-18, depending on method). Moreover, the reverse observation (i.e., higher proportions of novel genes outside of islands) never reached statistical significance in any organism examined. We show that this higher proportion of novel genes in predicted genomic islands is not due to less accurate gene prediction in genomic island regions, but likely reflects a genuine increase in novel genes in these regions for both bacteria and archaea. This represents the first comprehensive analysis of novel genes in prokaryotic genomic islands and provides clues regarding the origin of novel genes. Our collective results imply that there are different gene pools associated with recently horizontally transmitted genomic regions versus regions that are primarily vertically inherited. Moreover, there are more novel genes within the gene pool associated with genomic islands. Since genomic islands are frequently associated with a particular microbial adaptation, such as antibiotic resistance, pathogen virulence, or metal resistance, this suggests that microbes may have access to a larger “arsenal” of novel genes for adaptation than previously thought.
15-Deoxy-Δ12,14-Prostaglandin J2 Inhibits Macrophage Colonization by Salmonella enterica Serovar Typhimurium
Michelle M. C. Buckner, L. Caetano M Antunes, Navkiran Gill, Shannon L. Russell, Stephanie R. Shames, B. Brett Finlay
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0069759
Abstract: 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) is an anti-inflammatory downstream product of the cyclooxygenase enzymes. It has been implicated to play a protective role in a variety of inflammatory mediated diseases, including rheumatoid arthritis, neural damage, and myocardial infarctions. Here we show that 15d-PGJ2 also plays a role in Salmonella infection. Salmonella enterica Typhimurium is a Gram-negative facultative intracellular pathogen that is able to survive and replicate inside phagocytic immune cells, allowing for bacterial dissemination to systemic sites. Salmonella species cause a wide range of morbidity and mortality due to gastroenteritis and typhoid fever. Previously we have shown that in mouse models of typhoid fever, Salmonella infection causes a major perturbation in the prostaglandin pathway. Specifically, we saw that 15d-PGJ2 production was significantly increased in both liver and feces. In this work we show that 15d-PGJ2 production is also significantly increased in macrophages infected with Salmonella. Furthermore, we show that the addition of 15d-PGJ2 to Salmonella infected RAW264.7, J774, and bone marrow derived macrophages is sufficient to significantly reduce bacterial colonization. We also show evidence that 15d-PGJ2 is reducing bacterial uptake by macrophages. 15d-PGJ2 reduces the inflammatory response of these infected macrophages, as evidenced by a reduction in the production of cytokines and reactive nitrogen species. The inflammatory response of the macrophage is important for full Salmonella virulence, as it can give the bacteria cues for virulence. The reduction in bacterial colonization is independent of the expression of Salmonella virulence genes SPI1 and SPI2, and is independent of the 15d-PGJ2 ligand PPAR-γ. 15d-PGJ2 also causes an increase in ERK1/2 phosphorylation in infected macrophages. In conclusion, we show here that 15d-PGJ2 mediates the outcome of bacterial infection, a previously unidentified role for this prostaglandin.
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