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51. Molecular analysis as an aid to assess the public health risk of non-O157 shiga toxin-producing Escherichia coli strains

Author

Coombes, Brian K., Wickham, Mark E., Mascarenhas, Mariola, Gruenheid, Samantha, and Karmali, Mohamed A.

Subjects
Escherichia coli -- Physiological aspects, Escherichia coli -- Genetic aspects, Polymerase chain reaction -- Analysis, Disease transmission -- Research, Bacterial toxins -- Health aspects, Biological sciences
Abstract

The identification of three genomic islands encoding non-LEE effector (nle) genes and 14 individual nle genes in non-O157 shiga toxin-producing Escherichia coli (STEC) strains is reported. A molecular risk assessment method to rapidly recognize and respond to non-O157 STEC strains is presented.

Published
2008

53. Intestinal infection triggers Parkinson's disease-like symptoms in Pink1−/− mice.

Author

Matheoud, Diana, Cannon, Tyler, Voisin, Aurore, Penttinen, Anna-Maija, Ramet, Lauriane, Fahmy, Ahmed M., Ducrot, Charles, Laplante, Annie, Bourque, Marie-Josée, Zhu, Lei, Cayrol, Romain, Le Campion, Armelle, McBride, Heidi M., Gruenheid, Samantha, Trudeau, Louis-Eric, and Desjardins, Michel

Abstract

Parkinson's disease is a neurodegenerative disorder with motor symptoms linked to the loss of dopaminergic neurons in the substantia nigra compacta. Although the mechanisms that trigger the loss of dopaminergic neurons are unclear, mitochondrial dysfunction and inflammation are thought to have key roles1,2. An early-onset form of Parkinson's disease is associated with mutations in the PINK1 kinase and PRKN ubiquitin ligase genes3. PINK1 and Parkin (encoded by PRKN) are involved in the clearance of damaged mitochondria in cultured cells4, but recent evidence obtained using knockout and knockin mouse models have led to contradictory results regarding the contributions of PINK1 and Parkin to mitophagy in vivo5–8. It has previously been shown that PINK1 and Parkin have a key role in adaptive immunity by repressing presentation of mitochondrial antigens9, which suggests that autoimmune mechanisms participate in the aetiology of Parkinson's disease. Here we show that intestinal infection with Gram-negative bacteria in Pink1−/− mice engages mitochondrial antigen presentation and autoimmune mechanisms that elicit the establishment of cytotoxic mitochondria-specific CD8+ T cells in the periphery and in the brain. Notably, these mice show a sharp decrease in the density of dopaminergic axonal varicosities in the striatum and are affected by motor impairment that is reversed after treatment with l-DOPA. These data support the idea that PINK1 is a repressor of the immune system, and provide a pathophysiological model in which intestinal infection acts as a triggering event in Parkinson's disease, which highlights the relevance of the gut–brain axis in the disease10. In mice lacking PINK1, bacterial infection in the intestine results in mitochondrial antigen presentation and generation of CD8+ T cells, and infected mice develop motor impairments, suggesting that PINK1 suppresses autoimmunity. [ABSTRACT FROM AUTHOR]

Published
2019
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65. R-Spondin 2 signalling mediates susceptibility to fatal infectious diarrhoea

Author

Papapietro, Olivier, primary, Teatero, Sarah, additional, Thanabalasuriar, Ajitha, additional, Yuki, Kyoko E., additional, Diez, Eduardo, additional, Zhu, Lei, additional, Kang, Eugene, additional, Dhillon, Sandeep, additional, Muise, Aleixo M., additional, Durocher, Yves, additional, Marcinkiewicz, Martin M., additional, Malo, Danielle, additional, and Gruenheid, Samantha, additional

Published
2013
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68. An N-Ethyl-N-Nitrosourea (ENU)-Induced Dominant Negative Mutation in the JAK3 Kinase Protects against Cerebral Malaria

Author

Bongfen, Silayuv E., primary, Rodrigue-Gervais, Ian-Gael, additional, Berghout, Joanne, additional, Torre, Sabrina, additional, Cingolani, Pablo, additional, Wiltshire, Sean A., additional, Leiva-Torres, Gabriel A., additional, Letourneau, Louis, additional, Sladek, Robert, additional, Blanchette, Mathieu, additional, Lathrop, Mark, additional, Behr, Marcel A., additional, Gruenheid, Samantha, additional, Vidal, Silvia M., additional, Saleh, Maya, additional, and Gros, Philippe, additional

Published
2012
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72. Antibacterial autophagy occurs at PI(3)P-enriched domains of the endoplasmic reticulum and requires Rab1 GTPase

Author

Huang, Ju, primary, Birmingham, Cheryl L., additional, Shahnazari, Shahab, additional, Shiu, Jessica, additional, Zheng, Yiyu T., additional, Smith, Adam C., additional, Campellone, Kenneth G., additional, Heo, Won Do, additional, Gruenheid, Samantha, additional, Meyer, Tobias, additional, Welch, Matthew D., additional, Ktistakis, Nicholas T., additional, Kim, Peter K., additional, Klionsky, Daniel J, additional, and Brumell, John H., additional

Published
2011
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80. The Bacterial Virulence Factor NleA Inhibits Cellular Protein Secretion by Disrupting Mammalian COPII Function

Author

Kim, Jinoh, primary, Thanabalasuriar, Ajitha, additional, Chaworth-Musters, Tessa, additional, Fromme, J. Chris, additional, Frey, Elizabeth A., additional, Lario, Paula I., additional, Metalnikov, Pavel, additional, Rizg, Keyrillos, additional, Thomas, Nikhil A., additional, Lee, Sau Fung, additional, Hartland, Elizabeth L., additional, Hardwidge, Philip R., additional, Pawson, Tony, additional, Strynadka, Natalie C., additional, Finlay, B. Brett, additional, Schekman, Randy, additional, and Gruenheid, Samantha, additional

Published
2007
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85. Enterohemorrhagic Escherichia coli OmpT regulates outer membrane vesicle biogenesis.

Author

Premjani, Veena, Tilley, Derek, Gruenheid, Samantha, Le Moual, Hervé, and Samis, John A.

Subjects
ESCHERICHIA coli O157:H7, CELLULAR control mechanisms, DIARRHEA, LABORATORY mice, PROTEOLYTIC enzymes, PROTEASE inhibitors
Abstract

Enterohemorrhagic Escherichia coli (EHEC) infection from food or water often results in severe diarrheal disease and is a leading cause of death globally. Outer membrane vesicles (OMVs) secreted from E. coli induce lethality in mice. The omptin outer membrane protease OmpT from E. coli inactivates antimicrobial peptides and may enhance colonization of the uroepithelium, but its precise function remains unclear. Given OmpT is an outer membrane protease, we hypothesized it may have a role in OMV biogenesis. To further characterize the effect of OmpT on OMV production, a genetic approach using wild type, an ompT deletion mutant and an ompT overexpressing construct in EHEC were employed. ompT gene deletion markedly decreased OMV production and stainable lipid but increased vesicle diameter. Conversely, ompT overexpression profoundly increased OMV biogenesis but decreased stainable lipid, protein content, and vesicle diameter. Alterations in EHEC ompT gene expression have an impact on the biogenesis, composition, and size of OMVs. Changes in ompT gene expression may dynamically alter OMV formation, composition, and diameter in response to different host environments and contribute to cell-free intercellular communication to enhance bacterial growth and survival. [ABSTRACT FROM AUTHOR]

Published
2014
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89. Role of uropathogenic Escherichia coli OmpT in the resistance against human cathelicidin LL-37.

Author

Brannon, John R., Thomassin, Jenny-Lee, Desloges, Isabelle, Gruenheid, Samantha, and Moual, Hervé

Subjects
URINARY tract infections, BACTERICIDAL action, PEPTIDE antibiotics, ESCHERICHIA coli, CATHELICIDINS
Abstract

Uropathogenic Escherichia coli ( UPEC) strains are among the most prevalent causative agents of urinary tract infections. To establish infection, UPEC must overcome the bactericidal action of host antimicrobial peptides. Previously, the enterohaemorrhagic E. coli outer membrane protease, OmpT, was shown to degrade and inactivate the human antimicrobial peptide LL-37. This study aims to investigate the involvement of UPEC OmpT in LL-37 degradation. An ompT deletion mutant was generated in the prototypical UPEC strain CFT073. Western blot analysis showed that the OmpT protein level is moderate in CFT073. In agreement, OmpT was shown to partially cleave LL-37. However, no difference in the minimum inhibitory concentration of LL-37 was observed between CFT073 and the ompT mutant. Plasmid complementation of ompT, which led to increased OmpT levels, resulted in complete cleavage of LL-37 and a fourfold increase in the minimum inhibitory concentration. The analysis of other UPEC isolates showed similar OmpT activity levels as CFT073. Although UPEC OmpT can cleave LL-37, we conclude that the low level of OmpT limits its contribution to LL-37 resistance. Collectively, these data suggest that UPEC OmpT is likely accompanied by other LL-37 resistance mechanisms. [ABSTRACT FROM AUTHOR]

Published
2013
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92. The bacterial virulence factor NleA is required for the disruption of intestinal tight junctions by enteropathogenic Escherichia coli.

Author

Thanabalasuriar, Ajitha, Koutsouris, Athanasia, Weflen, Andrew, Mimee, Mark, Hecht, Gail, and Gruenheid, Samantha

Subjects
ESCHERICHIA coli, EPITHELIAL cells, SMALL intestine, PROTEINS, INTESTINES, CELLS
Abstract

Enteropathogenic Escherichia coli (EPEC) is a diarrhoeal pathogen that adheres to epithelial cells of the small intestine and uses a type III secretion system to inject effector proteins into host cells. EPEC infection leads to disruption of host intestinal tight junctions that are important for maintaining intestinal barrier function. This disruption is dependent on the bacterial type III secretion system, as well as the translocated effectors EspF and Map. Here we show that a third type III translocated bacterial effector protein, NleA, is also involved in tight junction disruption during EPEC infection. Using the drug Brefeldin A, we demonstrate that the effect of NleA on tight junction integrity is related to its inhibition of host cell protein trafficking through COPII-dependent pathways. These results suggest that NleA's striking effect on virulence is mediated, at least in part, via its role in disruption of intestinal barrier function. [ABSTRACT FROM AUTHOR]

Published
2010
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93. Dissecting virulence: Systematic and functional analyses of a pathogenicity island.

Author

Wanyin Deng, Jorge C., Puente, José L., Gruenheid, Samantha, Yuling Li, Vallance, Bruce A., Vázquez, Alejandra, Barba, Jeannette, Ibarra, J. Antonio, O'Donnell, Paul, Metalnikov, Pavel, Ashman, Keith, Lee, Sanson, Goode, David, Pawson, Tony, and Finlay, B. Brett

Subjects
FUNCTIONAL analysis, MOLECULES, SECRETION, ESCHERICHIA coli O157:H7, GENES, MICROBIAL virulence
Abstract

Bacterial pathogenicity islands (PAI) often encode both effector molecules responsible for disease and secretion systems that deliver these effectors to host cells. Human enterohemorrhagic Escherichia coli (EHEC), enteropathogenic E. coli, and the mouse pathogen Citrobacter rodentium (CR) possess the locus of enterocyte effacement (LEE) PAI. We systematically mutagenized all 41 CR LEE genes and functionally characterized these mutants in vitro and in a murine infection model. We identified 33 virulence factors, including two virulence regulators and a hierarchical switch for type III secretion. In addition, 7 potential type III effectors encoded outside the LEE were identified by using a proteomics approach. These non-LEE effectors are encoded by three uncharacterized PAIs in EHEC O157, suggesting that these PAIs act cooperatively with the LEE in pathogeneis. Our findings provide significant insights into bacterial virulence mechanisms and disease. [ABSTRACT FROM AUTHOR]

Published
2004
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94. OmpT Outer Membrane Proteases of Enterohemorrhagic and Enteropathogenic Escherichia coli Contribute Differently to the Degradation of Human LL-37

Author

Thomassin, Jenny-Lee, Brannon, John R., Gibbs, Bernard F., Gruenheid, Samantha, and Le Moual, Hervé

Abstract

Enterohemorrhagic Escherichia coli (EHEC) and enteropathogenic E. coli (EPEC) are food-borne pathogens that cause serious diarrheal diseases. To colonize the human intestine, these pathogens must overcome innate immune defenses such as antimicrobial peptides (AMPs). Bacterial pathogens have evolved various mechanisms to resist killing by AMPs, including proteolytic degradation of AMPs. To examine the ability of the EHEC and EPEC OmpT outer membrane (OM) proteases to degrade α-helical AMPs, ompT deletion mutants were generated. Determination of MICs of various AMPs revealed that both mutant strains are more susceptible than their wild-type counterparts to α-helical AMPs, although to different extents. Time course assays monitoring the degradation of LL-37 and C18G showed that EHEC cells degraded both AMPs faster than EPEC cells in an OmpT-dependent manner. Mass spectrometry analyses of proteolytic fragments showed that EHEC OmpT cleaves LL-37 at dibasic sites. The superior protection provided by EHEC OmpT compared to EPEC OmpT against α-helical AMPs was due to higher expression of the ompT gene and, in turn, higher levels of the OmpT protein in EHEC. Fusion of the EPEC ompT promoter to the EHEC ompT open reading frame resulted in decreased OmpT expression, indicating that transcriptional regulation of ompT is different in EHEC and EPEC. We hypothesize that the different contributions of EHEC and EPEC OmpT to the degradation and inactivation of LL-37 may be due to their adaptation to their respective niches within the host, the colon and small intestine, respectively, where the environmental cues and abundance of AMPs are different.

Published
2011

95. OmpT Outer Membrane Proteases of Enterohemorrhagic and Enteropathogenic Escherichia coliContribute Differently to the Degradation of Human LL-37

Author

Thomassin, Jenny-Lee, Brannon, John R., Gibbs, Bernard F., Gruenheid, Samantha, and Le Moual, Hervé

Abstract

ABSTRACTEnterohemorrhagic Escherichia coli(EHEC) and enteropathogenic E. coli(EPEC) are food-borne pathogens that cause serious diarrheal diseases. To colonize the human intestine, these pathogens must overcome innate immune defenses such as antimicrobial peptides (AMPs). Bacterial pathogens have evolved various mechanisms to resist killing by AMPs, including proteolytic degradation of AMPs. To examine the ability of the EHEC and EPEC OmpT outer membrane (OM) proteases to degrade α-helical AMPs, ompTdeletion mutants were generated. Determination of MICs of various AMPs revealed that both mutant strains are more susceptible than their wild-type counterparts to α-helical AMPs, although to different extents. Time course assays monitoring the degradation of LL-37 and C18G showed that EHEC cells degraded both AMPs faster than EPEC cells in an OmpT-dependent manner. Mass spectrometry analyses of proteolytic fragments showed that EHEC OmpT cleaves LL-37 at dibasic sites. The superior protection provided by EHEC OmpT compared to EPEC OmpT against α-helical AMPs was due to higher expression of the ompTgene and, in turn, higher levels of the OmpT protein in EHEC. Fusion of the EPEC ompTpromoter to the EHEC ompTopen reading frame resulted in decreased OmpT expression, indicating that transcriptional regulation of ompTis different in EHEC and EPEC. We hypothesize that the different contributions of EHEC and EPEC OmpT to the degradation and inactivation of LL-37 may be due to their adaptation to their respective niches within the host, the colon and small intestine, respectively, where the environmental cues and abundance of AMPs are different.

Published
2011
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96. The Cri1 locus is the common genetic cause of susceptibility to Citrobacter rodentiuminfection in C3H and FVB mouse strains.

Author

Teatero, Sarah Ann, Thomassin, Jenny-Lee, Zhu, Lei, Diez, Eduardo, Malo, Danielle, and Gruenheid, Samantha

Abstract

Citrobacter rodentium is a natural pathogen of mice that causes intestinal hyperplasia and colitis. Resistant strains such as C57BL/6J (B6) experience a self-limiting disease that peaks between one and two weeks post infection, followed by a clearing of the infection and complete recovery. However, the inbred mouse strains C3H/HeJ (C3), C3H/HeOuJ (C3Ou) and FVB/N (FVB) are highly susceptible to C. rodentium infection and develop more severe symptoms of disease leading to high rates of mortality during infection. We have recently demonstrated through a systematic genetics approach that a single locus on proximal chromosome 15 is responsible for the susceptibility of both C3 and C3Ou mice to C. rodentium infection. We have named the locus Citrobacter rodentium infection 1 (Cri1). Here we show that Cri1 also controls susceptibility to C. rodentium in FVB mice, using a targeted method of genotyping to stratify (B6 x FVB)F2 mice according to their genotype at Cri1. Mice that inherit two copies of the resistant B6 allele have 97% cumulative survival at day 30 post-infection, whereas those that inherit one or two copies of Cri1 from the FVB parent have significantly lower rates of survival (35% and 42%, respectively). These results provide evidence for a common genetic cause of fatal infectious colitis in C3, C3Ou and FVB mice following infection with Citrobacter rodentium.

Published
2011
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97. The bacterial virulence factor NleA's involvement in intestinal tight junction disruption during Enteropathogenic E. coliinfection is independent of its putative PDZ binding domain

Author

Thanabalasuriar, Ajitha, Koutsouris, Athanasia, Hecht, Gail, and Gruenheid, Samantha

Abstract

Enteropathogenic Escherichia coli(EPEC) is an enteric pathogen able to cause severe diarrhea. Once adhered to the small intestine, EPEC disrupts tight junctions that are important for intestinal barrier function. This disruption is dependent on the bacterial type III secretion system, as well as the translocated effectors EspF and Map. Recently we have shown that a third type III translocated bacterial effector protein, NleA, is also involved in tight junction disruption during EPEC infection. NleA has a predicted PDZ-binding domain at its C-terminus which is proposed to be involved in protein interactions with PDZ domain containing proteins. Since several PDZ-domain-containing proteins localize to tight junctions, we hypothesized that the PDZ-binding domain of NleA might be important for its role in tight junction disruption. However, here we show that a molecular variant of NleA lacking the PDZ-binding domain behaves indistinguishably from the wild-type protein with respect to disruption of tight junctions.

Published
2010
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100. Functional Complementation of the Yeast Divalent Cation Transporter Family SMFby NRAMP2, a Member of the Mammalian Natural Resistance-associated Macrophage Protein Family*

Author

Pinner, Elhanan, Gruenheid, Samantha, Raymond, Martine, and Gros, Philippe

Abstract

The mammalian NRAMPgene family has two members, NRAMP1and NRAMP2that encode integral membrane proteins. Nramp1 is expressed exclusively in macrophages where it is found in the phagosomal membrane, andNRAMP1mutations cause susceptibility to infection by abrogating the capacity of macrophages to control intracellular microbial replication. Nramp2 is highly similar to Nramp1, but is expressed in several tissues and cell types. The Nramp protein family is remarkably conserved throughout evolution, and recent data suggest that the mammalian Nramp2 and the yeast homologues Smf1 and Smf2 transport divalent cations. We tested whether structural similarity between the mammalian Nramp and the yeast Smf proteins results in functional complementation in yeast. Wild-type and mutant variants of the Nramp1 and Nramp2 proteins were expressed in a yeast mutant bearing null alleles at the SMF1and SMF2loci, and complementation of the phenotypes of this yeast mutant was investigated. Nramp2, but not Nramp1, was found to complement hypersensitivity to EGTA of the smf1/smf2mutant under oxidative stress conditions (methyl viologen). We also observed that the smf1/smf2double mutant is hypersensitive to growth at alkaline pH (pH 7.9) and that Nramp2 could complement this phenotype as well. Complementation by Nramp2 was specific and required a functional protein as independent mutations in residues highly conserved in all members of the Nramp family abrogated Nramp2 complementation. Since Mn2+was the only divalent cation capable of completely suppressing both the EGTA and pH phenotypes, our results suggest that Nramp2 can transport Mn2+in yeast.

Published
1997
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