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dc.contributor.authorWolanska, Dominika Paula
dc.date.accessioned2019-03-14T15:57:38Z
dc.date.available2019-03-14T15:57:38Z
dc.date.issued2019-07-20
dc.date.submitted2018-11-16
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/290550
dc.description.abstractA critical step in the pathogenesis of enteric bacteria such as Salmonella is entering the host cell. To achieve this, Salmonella inject effector proteins into the cytosol of the cell and manipulate the actin cytoskeleton, driving pathogen entry. Two of the delivered effectors, namely SopE and SopE2, activate host Rho GTPases and subsequently the Arp2/3 complex, which results in actin reorganisation. Whereas the role of SopE in promoting bacterial uptake is well-established, the precise function of SopE2 is not known. SopE2 was previously shown to activate Cdc42, which leads to the mobilisation of N-WASP and the resulting Arp2/3 complex-mediated actin assembly. This work establishes that the activity of SopE2 restricts excessive Salmonella uptake via the generation of actin structures that exhibit anti-phagocytic properties. The loss of SopE2 or N-WASP is associated with unrestricted pathogen entry, highlighting the importance of those proteins for limiting bacterial invasion. The C-terminal VCA domain of N-WASP is revealed as the key region for the formation of the invasion-limiting actin networks. Those SopE2- and N-WASP-generated actin structures also obstruct the translocation of effectors from the invading bacteria. The recruitment of different subunit isoforms by the Arp2/3 complex can also modulate Salmonella uptake, however the precise role of the VCA in that event remains elusive. Finally, the loss of N-WASP is associated with a reduction in the cellular content of filamentous actin and a decrease in focal adhesions made by the cell, which may also play a role in boosting pathogen uptake. Together these results outline a novel mechanism utilised by Salmonella to control its own invasion, which most likely sustains the viability of the host and thus maintains the replicative niche. This work also highlights the dual role of the actin network for promoting and inhibiting both effector translocation and the uptake of the pathogen.
dc.description.sponsorshipThe Wellcome Trust
dc.language.isoen
dc.rightsAll rights reserved
dc.rightsAll Rights Reserveden
dc.rights.urihttps://www.rioxx.net/licenses/all-rights-reserved/en
dc.subjectSalmonella
dc.subjectinvasion
dc.subjecteffector
dc.subjectN-WASP
dc.subjectactin
dc.titleEffector-driven actin reorganisation restricts Salmonella invasion.
dc.typeThesis
dc.type.qualificationlevelDoctoral
dc.type.qualificationnameDoctor of Philosophy (PhD)
dc.publisher.institutionUniversity of Cambridge
dc.publisher.departmentPathology
dc.date.updated2019-03-14T15:48:51Z
dc.identifier.doi10.17863/CAM.37778
dc.publisher.collegeClare
dc.type.qualificationtitlePhD in Biochemistry
cam.supervisorKoronakis, Vassilis
cam.thesis.fundingfalse
rioxxterms.freetoread.startdate2400-01-01


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