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Role of YopK in Yersinia resistance against polymorphonuclear leukocyte defense
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, Department of Molecular Biology (Faculty of Medicine).
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(English)Manuscript (preprint) (Other academic)
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-53703OAI: oai:DiVA.org:umu-53703DiVA: diva2:513897
Available from: 2012-04-04 Created: 2012-04-04 Last updated: 2012-04-04Bibliographically approved
In thesis
1. Role of the Yersinia protein YopK in microbe-host interactions
Open this publication in new window or tab >>Role of the Yersinia protein YopK in microbe-host interactions
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

There are three human pathogenic species of the genus Yersiniae: Yersinia pestis, Yersinia enterocolitica, and Yersinia pseudotuberculosis. To cause disease, these strains inhibit several key innate defense mechanisms, including phagocytosis, the critical process for bacterial clearance. The ability of Yersinia to evade the immune defense is dependent on delivery of virulence effectors, Yersinia outer proteins (Yops), into the interacting cell by a mechanism involving the type III secretion machinery. We have shown that the virulence protein YopK plays an important role in the control of Yop effector translocation via a feedback mechanism involving another virulence protein, YopE. We also found that YopK participated in regulation of Yop effector translocation by modulating level and ratio of the pore-forming proteins YopB and YopD in the target cell membrane. Further, using a yeast two-hybrid screen with YopK as a bait, the eukaryotic protein RACK1 was identified as a target for this virulence protein. We found that RACK1 was engaged upon Y. pseudotuberculosis-mediated β1-integrin activation, where it was recruited to phagocytic cups. Downregulation of RACK1 by RNAi resulted in a reduced ability of Y. pseudotuberculosis to block phagocytosis, indicating that RACK1 is required for efficient Yersinia-mediated antiphagocytosis. Based on our data, we suggest a model where Yersinia, via YopK, targets RACK1 to ensure a directed delivery of the Yop effectors to the “right place” where they bind to and inactivate their targets, resulting in efficient inhibition of phagocytosis.  

A yopK mutant strain over-delivers Yop effectors, but is still avirulent in mice, indicating that YopK is important for the fine-tuning of effector protein delivery during infection. To analyse this, we investigated the importance of YopK during in vivo infection. We found that a yopK mutant colonized Peyer’s patches and the mesenteric lymph node more rapidly compared to wild-type Y. pseudotuberculosis, but was unable to spread systemically to liver and spleen and cause full disease in mice. Further, we showed that a yopK mutant was able to colonize liver and spleen and cause full disease in mice lacking the main phagocytes, polymorphonuclear leukocytes (PMNs). We also showed that YopK was important for Yersinia-mediated silencing of the PMN response.

To summarize, we suggest that YopK is important for Yersinia to evade the PMN defense and thereby spread systemically and cause disease. YopK is proposed to do this by allowing a controlled, directed Yop effector delivery that is just sufficient to inhibit host immune defense mechanisms. The controlled and precise delivery of virulence effectors avoids inappropriate triggering of PMNs and thereby an enhanced immune response favoring the host.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2012. 58 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1492
Keyword
Yersinia, YopK, T3SS, antiphagocytosis, neutrophil, translocation, virulence
National Category
Cell and Molecular Biology
Research subject
Molecular Biology
Identifiers
urn:nbn:se:umu:diva-53585 (URN)978-91-7459-408-9 (ISBN)
Public defence
2012-04-27, Major Groove, Building 6L, Umeå University, Umeå, 09:00 (English)
Opponent
Supervisors
Funder
Swedish Research Council, K2008-58X-11222-14-3
Available from: 2012-04-04 Created: 2012-04-03 Last updated: 2012-04-04Bibliographically approved

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Thorslund, Sara EFahlgren, AnnaNilsson, KristinaUrban, ConstantinFällman, Maria
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