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Persistent infection by Yersinia pseudotuberculosis
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). (Maria Fällman)
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Enteropathogenic Yersinia species can infect many mammalian organs such as the small intestine, cecum, Peyer’s patches, liver, spleen, and lung and cause diseases that resemble a typhoid-like syndrome, as seen for other enteropathogens. We found that sublethal infection doses of Y. pseudotuberculosis gave rise to asymptomatic persistent infection in mice and identified the cecal lymphoid follicles as the primary site for colonization during persistence. Persistent Y. pseudotuberculosis is localized in the dome area, often in inflammatory lesions, as foci or as single cells, and also in neutrophil exudates in the cecal lumen. This new mouse model for bacterial persistence in cecum has potential as an investigative tool for deeper understanding of bacterial adaptation and host immune defense mechanisms during persistent infection. Here, we investigated the nature of the persistent infection established by Y. pseudotuberculosis in mouse cecal tissue using in vivo RNA-seq of bacteria during early and persistent stages of infection. Comparative analysis of the bacterial transcriptomes revealed that Y. pseudotuberculosis undergoes transcriptional reprogramming with drastic down-regulation of T3SS virulence genes during persistence in the cecum. At the persistent stage, the expression pattern in many respects resembles the pattern seen in vitro at 26°C. Genes that are up-regulated during persistence are genes involved in anaerobiosis, chemotaxis, and protection against oxidative and acidic stress, which indicates the influence of different environmental cues. We found that the Crp/CsrA/RovA regulatory cascades influence the pattern of bacterial gene expression during persistence. Furthermore, we show that ArcA, Fnr, FrdA, WrbA, RovA, and RfaH play critical roles in persistence. An extended investigation of the transcriptional regulator rfaH employing mouse infection studies, phenotypic characterizations, and RNA-seq transcriptomics analyses indicated that this gene product contributes to establishment of infection and confirmed that it regulates O-antigen biosynthesis genes in Y. pseudotuberculosis. The RNA-seq results also suggest that rfaH has a relatively global effect. Furthermore, we also found that the dynamics of the cecal tissue organization and microbial composition shows changes during different stages of the infection. Taken together, based on our findings, we speculate that this enteropathogen initiates infection by using its virulence factors in meeting the innate immune response in the cecal tissue. Later on, these factors lead to dysbiosis in the local microbiota and altered tissue organization. At later stages of the infection, the pathogen adapts to the environment in the cecum by reprogramming its transcriptome from a highly virulent mode to a more environmentally adaptable mode for survival and shedding. The in vivo transcriptomic analyses for essential genes during infections present strong candidates for novel targets for antimicrobials.

Place, publisher, year, edition, pages
Umeå: Umeå University , 2015. , 72 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1748
Keyword [en]
Persistent infection, RNA-seq, PMNs, Yersinia, Transcriptome, wrba, fnr, rovA, arcA, rfaH
National Category
Microbiology Bioinformatics and Systems Biology Biochemistry and Molecular Biology
Research subject
Molecular Biology; Infectious Diseases; Immunology
Identifiers
URN: urn:nbn:se:umu:diva-108837ISBN: 978-91-7601-335-9 (print)OAI: oai:DiVA.org:umu-108837DiVA: diva2:854110
Public defence
2015-10-09, Sal E04, byggnad 6E, NUS, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2015-09-18 Created: 2015-09-15 Last updated: 2015-09-16Bibliographically approved
List of papers
1. Colonization of cecum is important for development of persistent infection by Yersinia pseudotuberculosis
Open this publication in new window or tab >>Colonization of cecum is important for development of persistent infection by Yersinia pseudotuberculosis
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2014 (English)In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 82, no 8, 3471-3482 p.Article in journal (Refereed) Published
Abstract [en]

Yersiniosis is a human disease caused by the bacterium Yersinia pseudotuberculosis or Yersinia enterocolitica. The infection is usually resolved but can lead to postinfectious sequelae, including reactive arthritis and erythema nodosum. The commonly used Yersinia mouse infection model mimics acute infection in humans to some extent but leads to systemic infection and eventual death. Here, we analyzed sublethal infection doses of Y. pseudotuberculosis in mice in real time using bioluminescent imaging and found that infections using these lower doses result in extended periods of asymptomatic infections in a fraction of mice. In a search for the site for bacterial persistence, we found that the cecum was the primary colonization site and was the site where the organism resided during a 115-day infection period. Persistent infection was accompanied by sustained fecal shedding of cultivable bacteria. Cecal patches were identified as the primary site for cecal colonization during persistence. Y. pseudotuberculosis bacteria were present in inflammatory lesions, in localized foci, or as single cells and also in neutrophil exudates in the cecal lumen. The chronically colonized cecum may serve as a reservoir for dissemination of infection to extraintestinal sites, and a chronic inflammatory state may trigger the onset of postinfectious sequelae. This novel mouse model for bacterial persistence in cecum has potential as an investigative tool to unveil a deeper understanding of bacterial adaptation and host immune defense mechanisms during persistent infection.

Place, publisher, year, edition, pages
American Society for Microbiology, 2014
National Category
Immunology in the medical area Infectious Medicine
Identifiers
urn:nbn:se:umu:diva-91821 (URN)10.1128/IAI.01793-14 (DOI)000339161400035 ()
Available from: 2014-09-01 Created: 2014-08-18 Last updated: 2017-12-05Bibliographically approved
2. Reprogramming of Yersinia from Virulent to Persistent Mode Revealed by Complex In Vivo RNA-seq Analysis
Open this publication in new window or tab >>Reprogramming of Yersinia from Virulent to Persistent Mode Revealed by Complex In Vivo RNA-seq Analysis
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2015 (English)In: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 11, no 1, e1004600Article in journal (Refereed) Published
Abstract [en]

We recently found that Yersinia pseudotuberculosis can be used as a model of persistent bacterial infections. We performed in vivo RNA-seq of bacteria in small cecal tissue biopsies at early and persistent stages of infection to determine strategies associated with persistence. Comprehensive analysis of mixed RNA populations from infected tissues revealed that Y. pseudotuberculosis undergoes transcriptional reprogramming with drastic down-regulation of T3SS virulence genes during persistence when the pathogen resides within the cecum. At the persistent stage, the expression pattern in many respects resembles the pattern seen in vitro at 26oC, with for example, up-regulation of flagellar genes and invA. These findings are expected to have impact on future rationales to identify suitable bacterial targets for new antibiotics. Other genes that are up-regulated during persistence are genes involved in anaerobiosis, chemotaxis, and protection against oxidative and acidic stress, which indicates the influence of different environmental cues. We found that the Crp/CsrA/RovA regulatory cascades influence the pattern of bacterial gene expression during persistence. Furthermore, arcA, fnr, frdA, and wrbA play critical roles in persistence. Our findings suggest a model for the life cycle of this enteropathogen with reprogramming from a virulent to an adapted phenotype capable of persisting and spreading by fecal shedding.

Keyword
Persistent infection, RNA-seq, PMNs, Yersinia, Transcriptome, wrba, fnr, rovA, arcA, rfaH
National Category
Cell and Molecular Biology Biochemistry and Molecular Biology Bioinformatics and Systems Biology
Research subject
biology, Environmental Science
Identifiers
urn:nbn:se:umu:diva-100980 (URN)10.1371/journal.ppat.1004600 (DOI)000349106100030 ()25590628 (PubMedID)
Available from: 2015-03-16 Created: 2015-03-16 Last updated: 2017-12-04Bibliographically approved
3. Transcriptomic characterization of RfaH linked to persistent infection of Yersinia pseudotuberculosis
Open this publication in new window or tab >>Transcriptomic characterization of RfaH linked to persistent infection of Yersinia pseudotuberculosis
(English)Manuscript (preprint) (Other academic)
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-108872 (URN)
Available from: 2015-09-16 Created: 2015-09-16 Last updated: 2015-09-16

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Avican, Kemal

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Department of Molecular Biology (Faculty of Medicine)Umeå Centre for Microbial Research (UCMR)Molecular Infection Medicine Sweden (MIMS)
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