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Outer membrane proteins of Yersinia pestis: Ail and OmpA
Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). (Hans Wolf-Watz)
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

A vast number of studies have been completed on the virulence determinants of Yersinia spp.; however, the focus of many of these studies has been on the virulence plasmid and the plasmid-encoded Type three secretion system. Nevertheless, many chromosomal genes whose products are directly involved in virulence have also been identified. Some of these critical virulence determinants are outer membrane proteins. Outer membrane proteins of Gram-negative bacteria often have important physiological roles; however, some have also been found to be important for pathogenesis. In this thesis, we investigated two Yersinia. pestis outer membrane proteins, Ail and OmpA, and their roles in virulence. We provide evidence that Y. pestis Ail is a highly expressed outer membrane protein that is absolutely essential for Y. pestis to resist the killing action of the complement system present in human blood and tissues, as well as the blood and tissues of other mammalian hosts. Furthermore, Ail was important for virulence in a Y. pestis-Canorhabditis elegans model of infection.The work in this thesis also provided the first evidence that another surface-exposed outer membrane protein, termed OmpA, is required for both Yersinia pseudotuberculosis and Y. pestis to survive and proliferate intracellularly in macrophages. Finally, we provide evidence that Y. pestis has a functional small RNA MicA that controls the expression of OmpA. This is the first demonstration of sRNA-mediated regulation of a Yersinia virulence factor. This work has paved the way for future studies on the role of outer membrane proteins in virulence, particularly the role of Ail and OmpA.

Place, publisher, year, edition, pages
Umeå: Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet), Umeå universitet , 2010. , 89 p.
Series
Doctoral thesis / Umeå University, Department of Molecular Biology
Keyword [en]
Yersinia pestis, outer membrane proteins, Ail, ompA
National Category
Microbiology in the medical area
Research subject
Immunology; Microbiology; Infectious Diseases
Identifiers
URN: urn:nbn:se:umu:diva-33956ISBN: 978-91-7459-030-2 (print)OAI: oai:DiVA.org:umu-33956DiVA: diva2:318888
Public defence
2010-06-03, Molekylärbiologi, Major Groove, Byggnad 6L, Umeå universitet, Umeå, 10:00 (English)
Opponent
Supervisors
Available from: 2010-05-12 Created: 2010-05-11 Last updated: 2010-05-18Bibliographically approved
List of papers
1. Calcium-regulated type III secretion of Yop proteins by an Escherichia coli hha mutant carrying a Yersinia pestis pCD1 virulence plasmid.
Open this publication in new window or tab >>Calcium-regulated type III secretion of Yop proteins by an Escherichia coli hha mutant carrying a Yersinia pestis pCD1 virulence plasmid.
2006 (English)In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 74, no 2, 1381-6 p.Article in journal (Refereed) Published
Abstract [en]

A series of four large deletions that removed a total of ca. 36 kb of DNA from the ca. 70-kb Yersinia pestis pCD1 virulence plasmid were constructed using lambda Red-mediated recombination. Escherichia coli hha deletion mutants carrying the virulence plasmid with the deletions expressed a functional calcium-regulated type III secretion system. The E. coli hha/pCD1 system should facilitate molecular studies of the type III secretion process.

Identifiers
urn:nbn:se:umu:diva-33950 (URN)10.1128/IAI.74.2.1381-1386.2006 (DOI)16428789 (PubMedID)
Available from: 2010-05-11 Created: 2010-05-11 Last updated: 2017-12-12
2. Yersinia pestis kills Caenorhabditis elegans by a biofilm-independent process that involves novel virulence factors.
Open this publication in new window or tab >>Yersinia pestis kills Caenorhabditis elegans by a biofilm-independent process that involves novel virulence factors.
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2005 (English)In: EMBO Reports, ISSN 1469-221X, E-ISSN 1469-3178, Vol. 6, no 10, 992-997 p.Article in journal (Refereed) Published
Abstract [en]

It is known that Yersinia pestis kills Caenorhabditis elegans by a biofilm-dependent mechanism that is similar to the mechanism used by the pathogen to block food intake in the flea vector. Using Y. pestis KIM 5, which lacks the genes that are required for biofilm formation, we show that Y. pestis can kill C. elegans by a biofilm-independent mechanism that correlates with the accumulation of the pathogen in the intestine. We used this novel Y. pestis-C. elegans pathogenesis system to show that previously known and unknown virulence-related genes are required for full virulence in C. elegans. Six Y. pestis mutants with insertions in genes that are not related to virulence before were isolated using C. elegans. One of the six mutants carried an insertion in a novel virulence gene and showed significantly reduced virulence in a mouse model of Y. pestis pathogenesis. Our results indicate that the Y. pestis-C. elegans pathogenesis system that is described here can be used to identify and study previously uncharacterized Y. pestis gene products required for virulence in mammalian systems.

Identifiers
urn:nbn:se:umu:diva-33951 (URN)10.1038/sj.embor.7400516 (DOI)16170309 (PubMedID)
Available from: 2010-05-11 Created: 2010-05-11 Last updated: 2017-12-12
3. Resistance of Yersinia pestis to complement-dependent killing is mediated by the Ail outer membrane protein
Open this publication in new window or tab >>Resistance of Yersinia pestis to complement-dependent killing is mediated by the Ail outer membrane protein
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2008 (English)In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 76, no 2, 612-622 p.Article in journal (Refereed) Published
Abstract [en]

Yersinia pestis, the causative agent of plague, must survive in blood in order to cause disease and to be transmitted from host to host by fleas. Members of the Ail/Lom family of outer membrane proteins provide protection from complement-dependent killing for a number of pathogenic bacteria. The Y. pestis KIM genome is predicted to encode four Ail/Lom family proteins. Y. pestis mutants specifically deficient in expression of each of these proteins were constructed using lambda Red-mediated recombination. The Ail outer membrane protein was essential for Y. pestis to resist complement-mediated killing at 26 and 37 degrees C. Ail was expressed at high levels at both 26 and 37 degrees C, but not at 6 degrees C. Expression of Ail in Escherichia coli provided protection from the bactericidal activity of complement. High-level expression of the three other Y. pestis Ail/Lom family proteins (the y1682, y2034, and y2446 proteins) provided no protection against complement-mediated bacterial killing. A Y. pestis ail deletion mutant was rapidly killed by sera obtained from all mammals tested except mouse serum. The role of Ail in infection of mice, Caenorhabditis elegans, and fleas was investigated.

Identifiers
urn:nbn:se:umu:diva-33949 (URN)10.1128/IAI.01125-07 (DOI)18025094 (PubMedID)
Available from: 2010-05-11 Created: 2010-05-11 Last updated: 2017-12-12Bibliographically approved
4. Plasminogen activator Pla of Yersinia pestis utilizes murine DEC-205 (CD205) as a receptor to promote dissemination
Open this publication in new window or tab >>Plasminogen activator Pla of Yersinia pestis utilizes murine DEC-205 (CD205) as a receptor to promote dissemination
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2008 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 283, no 46, 31511-21 p.Article in journal (Refereed) Published
Abstract [en]

Yersinia pestis, a Gram-negative bacterium that causes bubonic and pneumonic plague, is able to rapidly disseminate to other parts of its mammalian hosts. Y. pestis expresses plasminogen activator (PLA) on its surface, which has been suggested to play a role in bacterial dissemination. It has been speculated that Y. pestis hijacks antigen-presenting cells, such as macrophages (MPhis) and dendritic cells, to be delivered to lymph nodes to initiate dissemination and infection. Both alveolar MPhis and pulmonary dendritic cells express a C-type lectin receptor, DEC-205 (CD205), which mediates antigen uptake and presentation. However, no ligand has been identified for DEC-205. In this study, we show that the invasion of alveolar MPhisby Y. pestis depends both in vitro and in vivo on the expression of PLA. DEC-205-expressing MPhis and transfectants, but not their negative counterparts, phagocytosed PLA-expressing Y. pestis and Escherichia coli K12 more efficiently than PLA-negative controls. The interactions between PLA-expressing bacteria and DEC-205-expressing transfectants or alveolar MPhis could be inhibited by an anti-DEC-205 antibody. Importantly, the blockage of the PLA-DEC-205 interaction reduced the dissemination of Y. pestis in mice. In conclusion, murine DEC-205 is a receptor for PLA of Y. pestis, and this host-pathogen interaction appears to play a key role in promoting bacterial dissemination.

National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-33948 (URN)10.1074/jbc.M804646200 (DOI)18650418 (PubMedID)
Available from: 2010-05-11 Created: 2010-05-11 Last updated: 2017-12-12Bibliographically approved
5. Intracellular survival of Yersinia spp. in macrophages requires outer membrane protein A (OmpA)
Open this publication in new window or tab >>Intracellular survival of Yersinia spp. in macrophages requires outer membrane protein A (OmpA)
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

In order to grow, multiply and disseminate within their hosts, Yersinia spp. must be able tosurvive encounters with host phagocytic cells such as macrophages. Yersinia pestis and Yersinia pseudotuberculosis both have the ability to survive within the phagolysosome of macrophages which may be important in early stages of the infection. These organisms also employ a T3SS toactively prevent phagocytosis. The ability of Y. pestis KIM mutants defective in the expression of outer membrane proteins to survive and proliferate in the presence of RAW 264.7 macrophage-like cells was evaluated. A Y. pestis KIM ΔompA mutant exhibited a significant defect in proliferation in the presence of macrophages. A similar defect could be produced by overexpressing the negative regulatory sRNA MicA, which down regulates OmpA expression. The ΔompA mutant exhibited no defect in the T3SS-mediated secretion or injection of Yops; however, this mutant showed a defect in intra macrophage survival in gentamicin protection assays. These studies suggest that the Yersinia spp. OmpA protein is a virulence factor that is required for survival within macrophages.

National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-33952 (URN)
Available from: 2010-05-11 Created: 2010-05-11 Last updated: 2010-06-03Bibliographically approved

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