Search

The mechanisms by which the gut luminal environment is disturbed by the immune system to foster pathogenic bacterial growth and survival remain incompletely understood. Here, we show that STAT2 dependent type I IFN signaling contributes to the inflammatory environment by disrupting hypoxia enabling the pathogenic S. Typhimurium to outgrow the microbiota. Stat2-/- mice infected with S. Typhimurium exhibited impaired type I IFN induced transcriptional responses in cecal tissue and reduced bacterial burden in the intestinal lumen compared to infected wild-type mice. Although inflammatory pathology was similar between wild-type and Stat2-/- mice, we observed decreased hypoxia in the gut tissue of Stat2-/- mice. Neutrophil numbers were similar in wild-type and Stat2-/- mice, yet Stat2-/- mice showed reduced levels of myeloperoxidase activity. In vitro, the neutrophils from Stat2-/- mice produced lower levels of superoxide anion upon stimulation with the bacterial ligand N-formylmethionyl-leucyl-phenylalanine (fMLP) in the presence of IFNα compared to neutrophils from wild-type mice, indicating that the neutrophils were less functional in Stat2-/- mice. Cytochrome bd-II oxidase-mediated respiration enhances S. Typhimurium fitness in wild-type mice, while in Stat2-/- deficiency, this respiratory pathway did not provide a fitness advantage. Furthermore, luminal expansion of S. Typhimurium in wild-type mice was blunted in Stat2-/- mice. Compared to wild-type mice which exhibited a significant perturbation in Bacteroidetes abundance, Stat2-/- mice exhibited significantly less perturbation and higher levels of Bacteroidetes upon S. Typhimurium infection. Our results highlight STAT2 dependent type I IFN mediated inflammation in the gut as a novel mechanism promoting luminal expansion of S. Typhimurium.

Inflammatory diseases of the gastrointestinal tract are frequently associated with dysbiosis, characterized by changes in gut microbial communities that include an expansion of facultative anaerobic bacteria of the Enterobacteriaceae family (phylum Proteobacteria). Here we show that a dysbiotic expansion of Enterobacteriaceae during gut inflammation could be prevented by tungstate treatment, which selectively inhibited molybdenum-cofactor-dependent microbial respiratory pathways that are operational only during episodes of inflammation. By contrast, we found that tungstate treatment caused minimal changes in the microbiota composition under homeostatic conditions. Notably, tungstate-mediated microbiota editing reduced the severity of intestinal inflammation in mouse models of colitis. We conclude that precision editing of the microbiota composition by tungstate treatment ameliorates the adverse effects of dysbiosis in the inflamed gut.

Since 1970, recognized political parties in the Canadian House of Commons have received funding for caucus research offices. Staffed by political partisans, research offices provide policy, communications, research and administrative support to party leaders and their parliamentary caucuses. This research note examines the evolving organization, work and function of these offices. It demonstrates, first, that the tendency towards centralization, evident in Canadian politics for decades, is clearly reflected in research offices' primary support for leaders rather than individual caucus members. Second, research offices are integral to parties' strategic communications and marketing efforts, and this, especially in government, often eclipses their policy contribution. Third, while the government party views caucus researchers as a useful supplement to public service and ministerial office resources, opposition parties rely heavily on their caucus research offices as their dominant source of staff capacity. Depuis l'annee 1970, les partis politiques reconnus dans la Chambre des communes du Canada ont recu des fonds pour les bureaux de recherche des caucus. Les bureaux de recherche, qui embauchent du personnel partisan, apportent du soutien pour les politiques, les communications, la recherche et l'administration aux chefs de partis et a leurs caucus parlementaires. Cette note de recherche etudie l'evolution de l'organisation, du travail et de la fonction de ces bureaux. Premierement, elle prouve que la tendance vers la centralisation, qui est manifeste dans la politique canadienne depuis des decennies, se reflete clairement dans le fait que le soutien principal des bureaux de recherche va aux chefs de parti, plutot qu'aux membres du caucus. Deuxiemement, le fait que particulierement au sein du gouvernement, les bureaux de recherche fassent partie integrante des communications strategiques et des campagnes de marketing des partis, porte souvent ombrage a leur contribution en matiere de politiques. Troisiemement, alors que le parti au pouvoir considere les analystes de caucus comme une aide utile au service public et aux bureaux ministeriels, les partis d'opposition comptent beaucoup sur leurs bureaux de recherche des caucus en tant que source principale de personnel., Introduction Apart from the governing party's access to non-partisan public servants and to partisan ministerial political staff, parliamentary caucus research offices represent one of the most important resources available to [...]

Salmonella enterica serovar Typhi (S. Typhi) causes typhoid fever, a disseminated infection, while the closely related pathogen S. enterica serovar Typhimurium (S. Typhimurium) is associated with a localized gastroenteritis in humans. Here we investigated whether both pathogens differ in the chemotactic response they induce in neutrophils using a single-cell experimental approach. Surprisingly, neutrophils extended chemotactic pseudopodia toward Escherichia coli and S. Typhimurium, but not toward S. Typhi. Bacterial-guided chemotaxis was dependent on the presence of complement component 5a (C5a) and C5a receptor (C5aR). Deletion of S. Typhi capsule biosynthesis genes markedly enhanced the chemotactic response of neutrophils in vitro. Furthermore, deletion of capsule biosynthesis genes heightened the association of S. Typhi with neutrophils in vivo through a C5aR-dependent mechanism. Collectively, these data suggest that expression of the virulence-associated (Vi) capsular polysaccharide of S. Typhi obstructs bacterial-guided neutrophil chemotaxis.

Political advisors in Canada are comparatively numerous and highly differentiated in role. Based on a recent survey, this article examines how senior ministerial policy advisors, a subset of the political staff community, perceive their support for ministers and their relationships with public servants. It finds that they increase ministers' policy capacity, encourage greater responsiveness from public servants, and generally feel that they enjoy good relations with officials and respect their role. Since much depends on advisors' personal maturity, however, the paper endorses the Trudeau government's release of a code of conduct for ministerial-exempt staff as a means of embedding accountability more deeply within political staff culture. Au Canada, les conseillers politiques sont comparativement nombreux et ont des roles fortement differencies. Base sur un recent sondage, cet article examine la question des hauts conseillers politiques ministeriels, un sous-ensemble du personnel ministeriel, et la maniere dont ceux-ci percoivent leur soutien aux ministres et leurs relations avec les fonctionnaires. Selon l'article, les conseillers politiques permettent aux ministres d'accroitre leur capacite en matiere d'elaboration de politiques, promeuvent le developpement de la receptivite chez les fonctionnaires, et ils ont generalement l'impression d'entretenir de bonnes relations avec les dirigeants et de respecter leur role. Cependant, comme beaucoup de choses dependent de la maturite personnelle des conseillers, l'article soutient la publication par le gouvernement Trudeau d'un code de conduite pour le personnel ministeriel exonere, comme moyen d'ancrer l'imputabilite plus profondement dans la culture du personnel ministeriel., Introduction Ministerial political advisors are an important but understudied influence alongside the traditional bilateral relationship between ministers and professional career public servants across Westminster-style parliamentary systems. While a growing corpus [...]

In 2010 Prime Minister Stephen Harper quietly created a system of Minister's Caucus Advisory Committees (MCACs), requiring ministers to consult with their backbench colleagues before taking policy proposals to cabinet. Based on interviews with Conservative MPs, ministers, political staffers and public servants, the paper argues that MCACs increase MPs' influence over government policy and enhance cohesion within the government's parliamentary caucus. By constraining ministers' policy freedom and providing the prime minister with regular political intelligence concerning policy proposals, MCACs reinforce his pre-eminence within cabinet and represent a significant innovation in the relationship between the executive and government caucus. Sommaire : En 2010, le Premier ministre Stephen Harper a discretement cree un systeme de comites consultatifs du caucus du ministre (CCCM), exigeant que les ministres consultent leurs collegues deputes d'arriere-banc avant de presenter leurs propositions de politiques au Cabinet. Reposant sur des entrevues avec des deputes conservateurs, des ministres, le personnel ministeriel et les fonctionnaires, l'article soutient que les CCCM accroissent l'influence des deputes sur la politique gouvernementale et ameliorent la cohesion au sein du caucus parlementaire du gouvernement. En limitant la liberte des ministres en matiere de politiques et en fournissant au Premier ministre des renseignements politiques reguliers concernant les enonces de politiques, les CCCM renforcent sa preeminence au sein du Cabinet et representent une importante innovation dans les relations entre l'executif et le caucus gouvernemental., Introduction Centralization of power has characterized successive Canadian federal governments since Pierre Trudeau (Savoie 1999; Bakvis 2001; Simpson 2001); but the 'politics of control' (Martin 2010) is widely perceived to [...]

Salmonella typhimurium causes a localized enteric infection in immunocompetent individuals, whereas HIV-infected individuals develop a life-threatening bacteremia. Here we show that simian immunodeficiency virus (SIV) infection results in depletion of T helper type 17 ([T.sub.H]17) cells in the ileal mucosa of rhesus macaques, thereby impairing mucosal barrier functions to S. typhimurium dissemination. In SIV-negative macaques, the gene expression profile induced by S. typhimurium in ligated ileal loops was dominated by [T.sub.H]17 responses, including the expression of interleukin-17 (IL-17) and IL-22. [T.sub.H]17 cells were markedly depleted in SIV-infected rhesus macaques, resulting in blunted [T.sub.H]17 responses to S. typhimurium infection and increased bacterial dissemination. IL-17 receptor-deficient mice showed increased systemic dissemination of S. typhimurium from the gut, suggesting that IL-17 deficiency causes defects in mucosal barrier function. We conclude that SIV infection impairs the IL-17 axis, an arm of the mucosal immune response preventing systemic microbial dissemination from the gastrointestinal tract., Although nontyphoidal Salmonella serotypes (NTS) are common agents causing acute food-borne disease worldwide, it is unusual to isolate them from the blood of adults, because in immunocompetent individuals these pathogens [...]

Like so many other Canadians, political staffers working for MPs and Senators on Parliament Hill and in constituency offices navigated some dramatic changes in their jobs in the early months of the global pandemic. In this article, the author reports on survey responses from 175 of these staffers and individual interviews with 10 MP staffers (representing all officially recognized parties in the House of Commons) and one Senate assistant. He notes that many staffers reported working longer hours and experiencing challenging work-life balance when working from home, frustration from the lack of information they received about government programs relating to the pandemic, and stress from the effects of isolation and fears about their health and safety when working from their offices. He concludes first by reiterating the important role political staffers, and particular frontline constituency office staff, play in assisting Canadians navigate the federal bureaucracy and, second, by cautioning parties and the parliamentary administration that counselling and services for staffers may be needed to minimize the harmful effects of this unprecedented period. [ABSTRACT FROM AUTHOR]

Copyright of Canadian Parliamentary Review / Revue Parlementaire Canadienne is the property of Canadian Parliamentary Review and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Escherichia coli strains may be beneficial or pathogenic. Many E. coli strains that cause human disease, especially those responsible for bacteremia and sepsis, express virulence factors that impart resistance to the complement system. The bacterial amyloid curli functions in bacterial adherence and enhances the formation of biofilms. Survival of curli-producing parental and curli-deficient mutant E. coli in the context of a human complement response was evaluated using an in vivo murine model of bacteremia. Results showed that curli production enhanced E. coli survival, which suggests that curli defends against complement-mediated killing. This observation was supported by the results of in vitro assays comparing bacterial survival in human serum. Experiments in which the classical or alternative complement pathways were blocked indicated that the classical pathway is the major contributor to complement activation and that curli inhibits this activity. Our analyses indicate that curli does not appear to play a role in protecting E. coli against alternative pathway complement activation. We found that curli increases binding of E. coli cells to complement component Complement component 1q (C1q) but does not affect Complement component 3b (C3b) binding. We conclude that curli defends E. coli against complement-mediated killing via inhibition of the classical complement pathway. [ABSTRACT FROM AUTHOR]

Salmonella enterica serovar Typhi (S. Typhi) causes typhoid fever, a disseminated infection, while the closely related pathogen S. enterica serovar Typhimurium (S. Typhimurium) is associated with a localized gastroenteritis in humans. Here we investigated whether both pathogens differ in the chemotactic response they induce in neutrophils using a single-cell experimental approach. Surprisingly, neutrophils extended chemotactic pseudopodia toward Escherichia coli and S. Typhimurium, but not toward S. Typhi. Bacterial-guided chemotaxis was dependent on the presence of complement component 5a (C5a) and C5a receptor (C5aR). Deletion of S. Typhi capsule biosynthesis genes markedly enhanced the chemotactic response of neutrophils in vitro. Furthermore, deletion of capsule biosynthesis genes heightened the association of S. Typhi with neutrophils in vivo through a C5aR-dependent mechanism. Collectively, these data suggest that expression of the virulence-associated (Vi) capsular polysaccharide of S. Typhi obstructs bacterial-guided neutrophil chemotaxis. [ABSTRACT FROM AUTHOR]

Unlike non-typhoidal Salmonella serotypes, S. enterica serotype Typhi does not elicit neutrophilic infiltrates in the human intestinal mucosa. The Vi capsule-encoding tviABCDEvexABCDE operon ( viaB locus) is a S. Typhi -specific DNA region preventing production of interleukin (IL)-8 during infection of intestinal epithelial cells. We elucidated the mechanism by which the viaB locus reduces IL-8 production in human colonic epithelial (T84) cells. A S. Typhi tviABCDEvexABCDE deletion mutant, but not a tviBCDEvexABCDE deletion mutant, elicited increased IL-8 production, which could be reduced to wild-type levels by introducing the cloned tviA regulatory gene. Thus, IL-8 expression in T84 cells was modulated by the TviA regulatory protein, but not by the Vi capsular antigen. Consistent with previous reports, IL-8 secretion by T84 cells was dependent on the presence of the flagellin protein FliC. TviA reduced expression of flhDC:: lacZ and fliC:: lacZ transcriptional fusions and secretion of FliC in S. Typhi. Introduction of tviA into S. enterica serotype Typhimurium reduced flagellin secretion and IL-8 expression. In conclusion, the viaB locus reduces IL-8 production in T84 cells by a TviA-mediated repression of flagellin secretion. Our data suggest that changes in flagella gene regulation played an important role during evolution of the human-adapted S. Typhi. [ABSTRACT FROM AUTHOR]

A massive neutrophil influx in the intestine is the histopathological hallmark of Salmonella enterica serovar Typhimurium-induced enterocolitis in humans. Two major hypotheses on the mechanism leading to neutrophil infiltration in the intestinal mucosa have emerged. One hypothesis suggests that S. enterica serovar Typhimurium takes an active role in triggering this host response by injecting proteins, termed effectors, into the host cell cytosol which induce a proinflammatory gene expression profile in the intestinal epithelium. The second hypothesis suggests a more passive role for the pathogen by proposing that bacterial invasion stimulates the innate pathways of inflammation because the pathogen-associated molecular patterns of S. enterica serovar Typhimurium are recognized by pathogen recognition receptors on cells in the lamina propria. A review of the current literature reveals that, while pathogen recognition receptors are clearly involved in eliciting neutrophil influx during S. enterica serovar Typhimurium infection, a direct contribution of effectors in triggering proinflammatory host cell responses cannot currently be ruled out. [ABSTRACT FROM AUTHOR]