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Cell type-specific effects of Yersinia pseudotuberculosis virulence effectors
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
2009 (English)In: Cellular Microbiology, ISSN 1462-5814, E-ISSN 1462-5822, Vol. 11, no 12, 1750-1767 p.Article 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.

Place, publisher, year, edition, pages
2009. Vol. 11, no 12, 1750-1767 p.
Keyword [en]
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
URN: urn:nbn:se:umu:diva-32248DOI: 10.1111/j.1462-5822.2009.01365.xPubMedID: 19681909OAI: diva2:302229
Available from: 2010-03-04 Created: 2010-03-04 Last updated: 2013-09-05Bibliographically approved
In thesis
1. Yersinia-phagocyte interactions during early infection
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. 59 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 1591
Yersinia, dendritic cell, macrophage, neutrophil, T3SS
National Category
Microbiology in the medical area Immunology in the medical area
Research subject
Infectious Diseases
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)
Swedish Research Council
Available from: 2013-09-05 Created: 2013-09-03 Last updated: 2013-10-10Bibliographically approved

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Fahlgren, AnnaWestermark, LindaAkopyan, KarenFällman, Maria
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Department of Molecular Biology (Faculty of Medicine)Molecular Infection Medicine Sweden (MIMS)Umeå Centre for Microbial Research (UCMR)
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Cellular Microbiology
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