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Host-pathogen interactions during Campylobacter and Yersinia infections
Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
2019 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

The innate immune system is known for protecting the host against invading pathogens, for instance enteropathogens infecting the gastrointestinal tract. The production of e.g. antimicrobial peptides, cytokines, and chemokines by innate immune cells and intestinal epithelial cells contribute to bacterial clearance. Given the significance of this system in overall defense, pathogens affect and/or manipulate immune cells and responses in favor of their own survival. This thesis focuses on how the Gram-negative enteropathogenic bacteria Yersinia pseudotuberculosis and Campylobacter jejuni affect the host, either directly via type 3 secretion system (T3SS) effector proteins or via outer membrane vesicles (OMVs), and how host factors potentially affect their virulence.

Yersinia pseudotuberculosis uses its T3SS to translocate virulence factors that disable various immune responses and subvert phagocytosis. Neutrophils are main target cells during Yersinia infection. They release granules that contain proteins with antimicrobial properties to the cell's exterior upon activation through a process called degranulation. We found that extracellular Y. pseudotuberculosis could prevent neutrophil degranulation upon cell contact. Prevention of degranulation was shown to be mediated via co-operative actions of the two anti-phagocytic Yersinia outer proteins YopH and YopE. Bacterial contact with neutrophils resulted in a transient inhibition of degranulation and further prevented degranulation upon subsequent contact with avirulent Y. pseudotuberculosis (lacking YopE and YopH) as well as Escherichia coli. Thus, Y. pseudotuberculosis impairs several neutrophil defense mechanisms to remain in the extracellular environment and to increase its survival during infection.

Campylobacter jejuni lacks a T3SS and appears to use OMVs and flagella as its main secretion apparatus. During passage through the intestine C. jejuni is exposed to bile, an important physiological component and part of the natural barrier of the intestine, and ability to resist bile is advantageous for C. jejuni survival. We investigated how C. jejuni OMV production and protein content is affected by bile. The main invasion and colonization of C. jejuni occurs in the lower part of the intestine where the concentration of bile is low compared with the proximal intestine. The OMV proteomic profiles were radically altered when bacteria were grown in low concentration of bile corresponding to cecal concentrations. Twenty-five present of the detected proteins of OMVs showed an altered abundance in the presence of low concentration of bile. In contrast, the overall proteome of the bacteria was unaffected. Moreover, OMVs frombile-exposed bacteria could enhance adhesion as well as invasion of bacteria into intestinal epithelial cells, suggesting a role of OMVs to the virulence of C. jejuni in the gut. The body temperature differs between the asymptomatic avian carriers of C. jejuni and humans, which develop symptomatic disease. We investigated whether the bacterial growth temperature affects the OMV proteome and found that 59 proteins were differentially expressed at 37°C. Among the higher abundant proteins, significantly more proteins were predicted to be related to virulence. Thus, temperature has an impact on the property of the OMVs, and this might affect the outcome of infection by C. jejuni in different hosts.

C. jejuni OMV interactions with innate immune cells were studied by analyses of OMV-mediated inflammasome activation. OMVs were found to induce ASC- and caspase-1-dependent inflammasome activation in murine and human macrophages and dendritic cells as well as in human neutrophils. While C. jejuni infection induced a low level of inflammasome-dependent cell death, OMV-induced inflammasome activation did not result in cell death. Thus, OMVs disseminate into tissue without bacteria can be a vehicle for virulence factors without inducing inflammatory cell death.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå University , 2019. , s. 79
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 2005
Nyckelord [en]
Campylobacter jejuni, Yersinia pseudotuberculosis, OMV, bile, temperature, proteomic
Nationell ämneskategori
Biokemi och molekylärbiologi Mikrobiologi Immunologi
Identifikatorer
URN: urn:nbn:se:umu:diva-155504ISBN: 978-91-7855-003-6 (tryckt)OAI: oai:DiVA.org:umu-155504DiVA, id: diva2:1280490
Disputation
2019-02-15, Hörsal D Unod T9, NUS, Umeå, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2019-01-25 Skapad: 2019-01-18 Senast uppdaterad: 2019-01-29Bibliografiskt granskad
Delarbeten
1. Yersinia pseudotuberculosis Blocks Neutrophil Degranulation
Öppna denna publikation i ny flik eller fönster >>Yersinia pseudotuberculosis Blocks Neutrophil Degranulation
2016 (Engelska)Ingår i: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 84, nr 12, s. 3369-3378Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Neutrophils are essential components of immunity and are rapidly recruited to infected or injured tissue. Upon their activation, neutrophils release granules to the cell's exterior, through a process called degranulation. These granules contain proteins with antimicrobial properties that help combat infection. The enteropathogenic bacterium Yersinia pseudotuberculosis successfully persists as an extracellular bacterium during infection by virtue of its translocation of virulence effectors (Yersinia outer proteins [Yops]) that act in the cytosol of host immune cells to subvert phagocytosis and proinflammatory responses. Here, we investigated the effect of Y. pseudotuberculosis on neutrophil degranulation upon cell contact. We found that virulent Y. pseudotuberculosis was able to prevent secondary granule release. The blocking effect was general, as the release of primary and tertiary granules was also reduced. Degranulation of secondary granules was also blocked in primed neutrophils, suggesting that this mechanism could be an important element of immune evasion. Further, wild-type bacteria conferred a transient block on neutrophils that prevented their degranulation upon contact with plasmid-cured, avirulent Y. pseudotuberculosis and Escherichia coli Detailed analyses showed that the block was strictly dependent on the cooperative actions of the two antiphagocytic effectors, YopE and YopH, suggesting that the neutrophil target structures constituting signaling molecules needed to initiate both phagocytosis and general degranulation. Thus, via these virulence effectors, Yersinia can impair several mechanisms of the neutrophil's antimicrobial arsenal, which underscores the power of its virulence effector machinery.

Nyckelord
Yersinia, neutrophil, degranulation
Nationell ämneskategori
Immunologi Mikrobiologi Annan biologi
Identifikatorer
urn:nbn:se:umu:diva-128892 (URN)10.1128/IAI.00760-16 (DOI)000390128700011 ()27620724 (PubMedID)
Tillgänglig från: 2016-12-19 Skapad: 2016-12-19 Senast uppdaterad: 2019-01-18Bibliografiskt granskad
2. Campylobacter jejuni bile exposure influences outer membrane vesicles protein content and bacterial interaction with epithelial cells
Öppna denna publikation i ny flik eller fönster >>Campylobacter jejuni bile exposure influences outer membrane vesicles protein content and bacterial interaction with epithelial cells
Visa övriga...
2018 (Engelska)Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, artikel-id 16996Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Campylobacter jejuni is a prevalent human pathogen and a major cause of bacterial gastroenteritis in the world. In humans, C. jejuni colonizes the intestinal tract and its tolerance to bile is crucial for bacteria to survive and establish infection. C. jejuni produces outer membrane vesicles (OMVs) which have been suggested to be involved in virulence. In this study, the proteome composition of C. jejuni OMVs in response to low concentration of bile was investigated. We showed that exposure of C. jejuni to low concentrations of bile, similar to the concentration in cecum, induced significant changes in the protein profile of OMVs released during growth without affecting the protein profile of the bacteria. This suggests that bile influences a selective packing of the OMVs after bacterial exposure to low bile. A low concentration of bile was found to increase bacterial adhesion to intestinal epithelial cells, likely by an enhanced hydrophobicity of the cell membrane following exposure to bile. The increased bacterial adhesiveness was not associated with increased invasion, instead bile exposure decreased C. jejuni invasion. OMVs released from bacteria upon exposure to low bile showed to increase both adhesion and invasion of non-bile-exposed bacteria into intestinal epithelial cells. These findings suggest that C. jejuni in environments with low concentrations of bile produce OMVs that facilitates colonization of the bacteria, and this could potentially contribute to virulence of C. jejuni in the gut.

Ort, förlag, år, upplaga, sidor
Nature Publishing Group, 2018
Nationell ämneskategori
Mikrobiologi Cellbiologi
Identifikatorer
urn:nbn:se:umu:diva-153787 (URN)10.1038/s41598-018-35409-0 (DOI)000450411700027 ()
Forskningsfinansiär
Carl Tryggers stiftelse för vetenskaplig forskning
Tillgänglig från: 2018-12-03 Skapad: 2018-12-03 Senast uppdaterad: 2019-01-18Bibliografiskt granskad
3. Accumulation of virulence-associated proteins in Campylobacter jejuni Outer Membrane Vesicles at human body temperature
Öppna denna publikation i ny flik eller fönster >>Accumulation of virulence-associated proteins in Campylobacter jejuni Outer Membrane Vesicles at human body temperature
2019 (Engelska)Ingår i: Journal of Proteomics, ISSN 1874-3919, E-ISSN 1876-7737, Vol. 195, s. 33-40Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Campylobacter jejuni is the major cause of bacterial gastroenteritis in humans. In contrast, colonization in avian hosts is asymptomatic. Body temperature differs between human (37 °C) and avian (42 °C) hosts, and bacterial growth in 37 °C is therefore a potential cue for higher virulence properties during human infection. The proteome of the bacteria was previously shown to be altered by temperature. Here we investigated whether temperature has an effect on the C. jejuni outer membrane vesicle (OMV) proteome, as OMVs are considered to be bacterial vehicles for protein delivery and might play a role during infection. OMVs isolated from C. jejuni strain 81-176 grown at 37 °C and 42 °C were analyzed by LC-ESI-MS/MS. 181 proteins were detected in both sample groups, one protein was exclusively present, and three were absent in OMVs from 37 °C. Of the 181 proteins, 59 were differentially expressed; 30 proteins were detected with higher abundance, and 29 proteins with lower abundance at 37 °C. Among the more highly abundant proteins, significantly more proteins were predicted to be associated with virulence. These data show that temperature has an impact on the property of the OMVs, and this might affect the outcome of colonization/infection by C. jejuni in different hosts.

Nyckelord
Campylobacter jejuni, OMVs, Proteomics, Temperature
Nationell ämneskategori
Mikrobiologi
Forskningsämne
mikrobiologi
Identifikatorer
urn:nbn:se:umu:diva-155499 (URN)10.1016/j.jprot.2019.01.005 (DOI)000459366000004 ()30641234 (PubMedID)
Tillgänglig från: 2019-01-18 Skapad: 2019-01-18 Senast uppdaterad: 2019-04-16Bibliografiskt granskad
4. Campylobacter jejuni outer membrane vesicles activate inflammasome without inducing cell death in immune cells
Öppna denna publikation i ny flik eller fönster >>Campylobacter jejuni outer membrane vesicles activate inflammasome without inducing cell death in immune cells
(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Nationell ämneskategori
Mikrobiologi
Identifikatorer
urn:nbn:se:umu:diva-155577 (URN)
Tillgänglig från: 2019-01-23 Skapad: 2019-01-23 Senast uppdaterad: 2019-01-23

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