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Murinization of internalin extends its receptor repertoire, altering Listeria monocytogenes cell tropism and host responses
- Source :
- PLoS Pathogens, PLoS Pathogens, 2013, 9 (5), ⟨10.1371/journal.ppat.1003381⟩, Plos Pathogens 5 (9), . (2013), PLoS Pathogens, Vol 9, Iss 5, p e1003381 (2013), PLoS Pathogens, Public Library of Science, 2013, 9 (5), ⟨10.1371/journal.ppat.1003381⟩
- Publication Year :
- 2013
- Publisher :
- HAL CCSD, 2013.
-
Abstract
- Listeria monocytogenes (Lm) is an invasive foodborne pathogen that leads to severe central nervous system and maternal-fetal infections. Lm ability to actively cross the intestinal barrier is one of its key pathogenic properties. Lm crosses the intestinal epithelium upon the interaction of its surface protein internalin (InlA) with its host receptor E-cadherin (Ecad). InlA-Ecad interaction is species-specific, does not occur in wild-type mice, but does in transgenic mice expressing human Ecad and knock-in mice expressing humanized mouse Ecad. To study listeriosis in wild-type mice, InlA has been “murinized” to interact with mouse Ecad. Here, we demonstrate that, unexpectedly, murinized InlA (InlAm) mediates not only Ecad-dependent internalization, but also N-cadherin-dependent internalization. Consequently, InlAm-expressing Lm targets not only goblet cells expressing luminally-accessible Ecad, as does Lm in humanized mice, but also targets villous M cells, which express luminally-accessible N-cadherin. This aberrant Lm portal of entry results in enhanced innate immune responses and intestinal barrier damage, both of which are not observed in wild-type Lm-infected humanized mice. Murinization of InlA therefore not only extends the host range of Lm, but also broadens its receptor repertoire, providing Lm with artifactual pathogenic properties. These results challenge the relevance of using InlAm-expressing Lm to study human listeriosis and in vivo host responses to this human pathogen.<br />Author Summary Co-evolution of microbes with their hosts can select stringently specific host-microbe interactions at the cell, tissue and species levels. Listeria monocytogenes (Lm) is a foodborne pathogen that causes a deadly systemic infection in humans. Lm crosses the intestinal epithelium upon the interaction of its surface protein InlA with E-cadherin (Ecad). InlA-Ecad interaction is species-specific, does not occur in wild-type mice, but does in transgenic mice expressing human Ecad and knock-in mice expressing humanized mouse Ecad. To study listeriosis in wild-type mice, InlA has been “murinized” to interact with mouse Ecad. Here, we demonstrate that in addition to interacting with mouse Ecad, InlAm also uses N-cadherin as a receptor, whereas InlA does not. This artifactual InlAm-N-cadherin interaction promotes bacterial translocation across villous M cells, a cell type which is not targeted by InlA-expressing bacteria. This leads to intestinal inflammation and intestinal barrier damage, both of which are not seen in humans and humanized mouse models permissive to InlA-Ecad interaction. These results challenge the relevance of using InlAm-expressing Lm as a model to study human listeriosis and host responses to this pathogen. They also illustrate that caution must be exercised before using “murinized” pathogens to study human infectious diseases.
- Subjects :
- [SDV]Life Sciences [q-bio]
medicine.disease_cause
Mice
Intestinal mucosa
[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases
Listeriosis
Intestinal Mucosa
Biology (General)
Internalization
media_common
0303 health sciences
Cadherins
Intestinal epithelium
3. Good health
[SDV] Life Sciences [q-bio]
Infectious Diseases
[SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology
[SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases
Medicine
Female
[SDV.MP.PAR] Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology
Research Article
QH301-705.5
media_common.quotation_subject
Immunology
Mice, Transgenic
Biology
Microbiology
03 medical and health sciences
Model Organisms
Bacterial Proteins
Listeria monocytogenes
Virology
Genetics
medicine
Animals
Humans
Internalin
[SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology
Molecular Biology
[SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology
Tropism
030304 developmental biology
Innate immune system
030306 microbiology
RC581-607
bacterial infections and mycoses
Disease Models, Animal
Humanized mouse
Parasitology
Immunologic diseases. Allergy
Subjects
Details
- Language :
- English
- ISSN :
- 15537366 and 15537374
- Database :
- OpenAIRE
- Journal :
- PLoS Pathogens, PLoS Pathogens, 2013, 9 (5), ⟨10.1371/journal.ppat.1003381⟩, Plos Pathogens 5 (9), . (2013), PLoS Pathogens, Vol 9, Iss 5, p e1003381 (2013), PLoS Pathogens, Public Library of Science, 2013, 9 (5), ⟨10.1371/journal.ppat.1003381⟩
- Accession number :
- edsair.doi.dedup.....5d915f3fb4999271306cac0b63d34b57