umu.sePublications
Change search
Link to record
Permanent link

Direct link
BETA
Westermark, Linda
Publications (6 of 6) Show all publications
Fahlgren, A., Avican, K., Westermark, L., Nordfelth, R. & Fällman, M. (2014). Colonization of cecum is important for development of persistent infection by Yersinia pseudotuberculosis. Infection and Immunity, 82(8), 3471-3482
Open this publication in new window or tab >>Colonization of cecum is important for development of persistent infection by Yersinia pseudotuberculosis
Show others...
2014 (English)In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 82, no 8, p. 3471-3482Article 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: 2018-06-07Bibliographically approved
Westermark, L. (2013). Yersinia-phagocyte interactions during early infection. (Doctoral dissertation). Umeå: Umeå universitet
Open this publication in new window or tab >>Yersinia-phagocyte interactions during early infection
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Pathogenic Gram-negative Yersinia species preferentially target and inactivate phagocytic cells of the innate immune defense by translocation of effector Yersinia outer proteins (Yops) into the cells via a type III secretion system. This indicates that inactivation and avoidance of the early innate immune response is an efficient way for Yersinia species to avoid elimination and to cause diseases ranging from mild gastroenteritis (Y. pseudotuberculosis and Y. enterocolitica) to plague (Y. pestis). In this project, we aimed to study the interaction between enteropathogenic Y. pseudotuberculosis and phagocytic cells during early infection.

In situ interaction studies on infected intestinal tissues showed that Y. pseudotuberculosis mainly interacts with dendritic cells (DCs) in lymphoid tissues of the intestine during initial infection. After massive recruitment of polymorphonuclear neutrophils (PMNs) to the infected tissues, wild-type (wt) bacteria also interacted with this phagocyte. In contrast to the wt, mutants lacking the anti-phagocytic effectors YopH and YopE are avirulent in mice and unable to spread systemically. Interestingly, our interaction assay showed that these mutants not only interacted with DCs, but also with PMNs during the initial stage of infection. Thus, indicating that Y. pseudotuberculosis can avoid interaction with PMNs during early infection and that this is Yop-dependent. In a phagocytosis assay Y. pseudotuberculosis was demonstrated to inhibit internalization by DCs in a YopE-dependent manner, while both YopH and YopE were shown to be involved in the blocking of phagocytosis by macrophages and PMNs. Thus, indicating that YopH has cell type-specific effects. To further investigate the role of DCs during initial stages of infection, a mouse DC depletion model (CD11c-DTRtg) was applied. However, the DTx-mediated depletion of DCs in CD11c-DTRtg mice induced neutrophilia and the model could not give a definite answer to whether DCs play an important role in either restricting or stimulating progression of Y. pseudotuberculosis infection. To investigate involvement of PMNs during early infection mice were injected with the depleting antibody α-Ly6G. In absence of PMNs wt, as well as yopH and yopE mutants became more virulent, which further supports the importance of these Yops for the ability of Y. pseudotuberculosis to disseminate from the initial infection sites in the intestine to cause systemic disease.

In summary, our studies show that inhibiting internalization and maturation of DCs and avoiding phagocytosis by and interaction with macrophages and PMNs during the early stages of infection are important virulence strategies for Y. pseudotuberculosis to be able to colonize tissues, proliferate and disseminate systemically.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2013. p. 59
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1591
Keywords
Yersinia, dendritic cell, macrophage, neutrophil, T3SS
National Category
Microbiology in the medical area Immunology in the medical area
Research subject
Infectious Diseases
Identifiers
urn:nbn:se:umu:diva-79852 (URN)978-91-7459-713-4 (ISBN)
Public defence
2013-09-27, N320, Naturvetarhuset, Umeå universitet, Umeå, 13:00 (English)
Opponent
Supervisors
Funder
Swedish Research Council
Available from: 2013-09-05 Created: 2013-09-03 Last updated: 2018-06-08Bibliographically approved
Westermark, L., Fahlgren, A. & Fällman, M. (2012). Immune response to diphtheria toxin-mediated depletion complicates the use of the CD11c-DTRtg model for studies of bacterial gastrointestinal infections. Paper presented at European Congress of Immunology, SEP 05-08, 2012, Glasgow, SCOTLAND. Immunology, 137(S1), 271-271
Open this publication in new window or tab >>Immune response to diphtheria toxin-mediated depletion complicates the use of the CD11c-DTRtg model for studies of bacterial gastrointestinal infections
2012 (English)In: Immunology, ISSN 0019-2805, E-ISSN 1365-2567, Vol. 137, no S1, p. 271-271Article in journal, Meeting abstract (Other academic) Published
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-61200 (URN)10.1111/imm.12002 (DOI)000309189102005 ()
Conference
European Congress of Immunology, SEP 05-08, 2012, Glasgow, SCOTLAND
Available from: 2012-11-08 Created: 2012-11-07 Last updated: 2018-06-08Bibliographically approved
Westermark, L., Fahlgren, A. & Fällman, M. (2012). Immune response to diphtheria toxin-mediated depletion complicates the use of the CD11c-DTR(tg) model for studies of bacterial gastrointestinal infections. Microbial Pathogenesis, 53(3-4), 154-161
Open this publication in new window or tab >>Immune response to diphtheria toxin-mediated depletion complicates the use of the CD11c-DTR(tg) model for studies of bacterial gastrointestinal infections
2012 (English)In: Microbial Pathogenesis, ISSN 0882-4010, E-ISSN 1096-1208, Vol. 53, no 3-4, p. 154-161Article in journal (Refereed) Published
Abstract [en]

Dendritic cells play an important role in the immune response against pathogens, as they are responsible for the activation and control of both innate and adaptive immune responses. The CD11c-DTR(tg) model, which allows transient elimination of dendritic cells by diphtheria toxin-treatment (DTx), has been extensively used to study the importance of this immune cell during steady-state and infection conditions in mice. Infecting dendritic cell-depleted mice orally with Yersinia pseudotuberculosis results in a markedly reduced level of infection compared with infection of non-depleted mice. We show here that it is not the lack of dendritic cells per se that is responsible for the reduced infection efficiency, instead it is an immune response induced by the DTx-treatment that prevents the bacteria from establishing colonization in Peyer's patches. The DTx-induced depletion initiates an immune response, with elevated serum levels of keratinocyte-derived cytokine (KC) and recruitment of polymorphonuclear neutrophils to dendritic cell-containing organs, such as Peyer's patches. Since the window for having an animal depleted of dendritic cells is limited in time for this model, the DTx-mediated effect on the immune system complicates the use of this model in studies of early events during bacterial infections.

Keywords
Pathogen-Host Interaction, Virulence Factor, Viruelnce, Bacteria
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-61272 (URN)10.1016/j.micpath.2012.06.004 (DOI)22771374 (PubMedID)
Available from: 2012-11-07 Created: 2012-11-07 Last updated: 2018-06-08Bibliographically approved
Fahlgren, A., Westermark, L., Akopyan, K. & Fällman, M. (2009). Cell type-specific effects of Yersinia pseudotuberculosis virulence effectors. Cellular Microbiology, 11(12), 1750-1767
Open this publication in new window or tab >>Cell type-specific effects of Yersinia pseudotuberculosis virulence effectors
2009 (English)In: Cellular Microbiology, ISSN 1462-5814, E-ISSN 1462-5822, Vol. 11, no 12, p. 1750-1767Article in journal (Refereed) Published
Abstract [en]

One important feature of Yersinia pseudotuberculosis that enables resistance against the host immune defence is delivery of the antiphagocytic effectors YopH and YopE into phagocytic cells. The tyrosine phosphatase YopH influences integrin signalling, and YopE impairs cytoskeletal dynamics by inactivating Rho GTPases. Here, we report the impact of these effectors on internalization by dendritic cells (DCs), which internalize antigens to orchestrate host immune responses. We found that this pathogen resists internalization by DCs via YopE. YopH that is important for blocking phagocytosis by macrophages and neutrophils and which is also present inside the DCs does not contribute to the resistance. However, the YopH targets Fyb and p130Cas show higher expression levels in macrophages than in DCs. Furthermore, live cell microscopy revealed that the cells internalize Y. pseudotuberculosis in different ways: the macrophages utilize a locally restricted receptor-mediated zipper mechanism, whereas DCs utilize macropinocytosis involving constitutive ruffling that randomly catches bacteria into membrane folds. We conclude that YopH impacts early phagocytic signalling from the integrin receptor to which the bacterium binds and that this tight receptor-mediated stimulation is absent in DC macropinocytosis. Inactivation of cytoskeletal dynamics by YopE affects ruffling activity and hence also internalization. The different modes of internalization can be coupled to the major functions of these respective cell types: elimination by phagocytosis and antigen sampling.

Keywords
Antibodies, Blocking/pharmacology, Antigens, Bacterial/genetics/*physiology, Antigens, CD11b/immunology/*physiology, Antigens, CD18/immunology/*physiology, Bacterial Adhesion/immunology, Bacterial Outer Membrane Proteins/genetics/*physiology, Carrier Proteins/genetics/*physiology, Complement Activation/immunology, Humans, Immunosuppressive Agents/pharmacology, Neutrophils/*immunology/metabolism/*microbiology, Phagocytosis/*immunology, Phosphorylation, Protein-Tyrosine Kinases/physiology, Receptors, Complement/antagonists & inhibitors/physiology, Signal Transduction/*immunology, Streptococcus pyogenes/genetics/*immunology, Tyrosine/metabolism, cdc42 GTP-Binding Protein/metabolism, rac GTP-Binding Proteins/metabolism
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-32248 (URN)10.1111/j.1462-5822.2009.01365.x (DOI)19681909 (PubMedID)
Available from: 2010-03-04 Created: 2010-03-04 Last updated: 2018-06-08Bibliographically approved
Westermark, L., Fahlgren, A. & Fällman, M.Yersinia pseudotuberculosis efficiently avoids polymorphonuclear neutrophils during early infection.
Open this publication in new window or tab >>Yersinia pseudotuberculosis efficiently avoids polymorphonuclear neutrophils during early infection
(English)Manuscript (preprint) (Other academic)
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-79989 (URN)
Available from: 2013-09-05 Created: 2013-09-05 Last updated: 2018-06-08Bibliographically approved
Organisations

Search in DiVA

Show all publications