Lawsonia intracellularis exploits β-catenin/Wnt and Notch signalling pathways during infection of intestinal crypt to alter cell homeostasis and promote cell proliferation
Lawsonia intracellularis is an obligate intracellular bacterial pathogen that causes proliferative enteropathy (PE) in pigs. L. intracellularis infection causes extensive intestinal crypt cell proliferation and inhibits secretory and absorptive cell differentiation. However, the affected host upstre...
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| Veröffentlicht in: | PloS one 2017-03, Vol.12 (3), p.e0173782-e0173782 |
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| description | Lawsonia intracellularis is an obligate intracellular bacterial pathogen that causes proliferative enteropathy (PE) in pigs. L. intracellularis infection causes extensive intestinal crypt cell proliferation and inhibits secretory and absorptive cell differentiation. However, the affected host upstream cellular pathways leading to PE are still unknown. β-catenin/Wnt signalling is essential in maintaining intestinal stem cell (ISC) proliferation and self-renewal capacity, while Notch signalling governs differentiation of secretory and absorptive lineage specification. Therefore, in this report we used immunofluorescence (IF) and quantitative reverse transcriptase PCR (RTqPCR) to examine β-catenin/Wnt and Notch-1 signalling levels in uninfected and L. intracellularis infected pig ileums at 3, 7, 14, 21 and 28 days post challenge (dpc). We found that while the significant increase in Ki67+ nuclei in crypts at the peak of L. intracellularis infection suggested enhanced cell proliferation, the expression of c-MYC and ASCL2, promoters of cell growth and ISC proliferation respectively, was down-regulated. Peak infection also coincided with enhanced cytosolic and membrane-associated β-catenin staining and induction of AXIN2 and SOX9 transcripts, both encoding negative regulators of β-catenin/Wnt signalling and suggesting a potential alteration to β-catenin/Wnt signalling levels, with differential regulation of the expression of its target genes. We found that induction of HES1 and OLFM4 and the down-regulation of ATOH1 transcript levels was consistent with the increased Notch-1 signalling in crypts at the peak of infection. Interestingly, the significant down-regulation of ATOH1 transcript levels coincided with the depletion of MUC2 expression at 14 dpc, consistent with the role of ATOH1 in promoting goblet cell maturation. The lack of significant change to LGR5 transcript levels at the peak of infection suggested that the crypt hyperplasia was not due to the expansion of ISC population. Overall, simultaneous induction of Notch-1 signalling and the attenuation of β-catenin/Wnt pathway appear to be associated with the inhibition of goblet cell maturation and enhanced crypt cell proliferation at the peak of L. intracellularis infection. Moreover, the apparent differential regulation of apoptosis between crypt and lumen cells together with the strong induction of Notch-1 signalling and the enhanced SOX9 expression along crypts 14 dpc suggest an expansion of actively d |
| doi_str_mv | 10.1371/journal.pone.0173782 |
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L. intracellularis infection causes extensive intestinal crypt cell proliferation and inhibits secretory and absorptive cell differentiation. However, the affected host upstream cellular pathways leading to PE are still unknown. β-catenin/Wnt signalling is essential in maintaining intestinal stem cell (ISC) proliferation and self-renewal capacity, while Notch signalling governs differentiation of secretory and absorptive lineage specification. Therefore, in this report we used immunofluorescence (IF) and quantitative reverse transcriptase PCR (RTqPCR) to examine β-catenin/Wnt and Notch-1 signalling levels in uninfected and L. intracellularis infected pig ileums at 3, 7, 14, 21 and 28 days post challenge (dpc). We found that while the significant increase in Ki67+ nuclei in crypts at the peak of L. intracellularis infection suggested enhanced cell proliferation, the expression of c-MYC and ASCL2, promoters of cell growth and ISC proliferation respectively, was down-regulated. Peak infection also coincided with enhanced cytosolic and membrane-associated β-catenin staining and induction of AXIN2 and SOX9 transcripts, both encoding negative regulators of β-catenin/Wnt signalling and suggesting a potential alteration to β-catenin/Wnt signalling levels, with differential regulation of the expression of its target genes. We found that induction of HES1 and OLFM4 and the down-regulation of ATOH1 transcript levels was consistent with the increased Notch-1 signalling in crypts at the peak of infection. Interestingly, the significant down-regulation of ATOH1 transcript levels coincided with the depletion of MUC2 expression at 14 dpc, consistent with the role of ATOH1 in promoting goblet cell maturation. The lack of significant change to LGR5 transcript levels at the peak of infection suggested that the crypt hyperplasia was not due to the expansion of ISC population. Overall, simultaneous induction of Notch-1 signalling and the attenuation of β-catenin/Wnt pathway appear to be associated with the inhibition of goblet cell maturation and enhanced crypt cell proliferation at the peak of L. intracellularis infection. Moreover, the apparent differential regulation of apoptosis between crypt and lumen cells together with the strong induction of Notch-1 signalling and the enhanced SOX9 expression along crypts 14 dpc suggest an expansion of actively dividing transit amplifying and/or absorptive progenitor cells and provide a potential basis for understanding the development and maintenance of PE.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0173782</identifier><identifier>PMID: 28323899</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Absorptivity ; Animals ; Apoptosis ; Apoptosis - physiology ; Bacteria ; Bacterial infections ; beta Catenin - metabolism ; Biology and Life Sciences ; c-Myc protein ; Cancer ; Caspase 3 - metabolism ; Cell cycle ; Cell differentiation ; Cell division ; Cell growth ; Cell proliferation ; Cell Proliferation - physiology ; Cell self-renewal ; Cells (biology) ; Crypts ; Desulfovibrionaceae Infections - metabolism ; Desulfovibrionaceae Infections - pathology ; Diarrhea ; Differentiation (biology) ; Disease Progression ; Female ; Gamma rays ; Gastroenterology ; Gene expression ; Homeostasis ; Homeostasis - physiology ; Hyperplasia ; Ileum - metabolism ; Ileum - microbiology ; Ileum - pathology ; Immunofluorescence ; Infections ; Intestine ; Lawsonia ; Lawsonia Bacteria ; Ligands ; Male ; Math1 protein ; Maturation ; Medicine and Health Sciences ; Mucin-2 - metabolism ; Myc protein ; Notch protein ; Notch1 protein ; Nuclei ; Progenitor cells ; Random Allocation ; Receptors, Notch - metabolism ; Research and analysis methods ; RNA-directed DNA polymerase ; Salmonella ; Signal transduction ; Signaling ; Small intestine ; Sox9 protein ; SOX9 Transcription Factor - metabolism ; Stem cells ; Studies ; Sus scrofa ; Transcription ; Wnt protein ; Wnt Signaling Pathway - physiology ; β-Catenin</subject><ispartof>PloS one, 2017-03, Vol.12 (3), p.e0173782-e0173782</ispartof><rights>2017 Huan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2017 Huan et al 2017 Huan et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c526t-b58712c12b8267aff429c2410742a11328872d501d34159fad95fc6c3dc03da23</citedby><cites>FETCH-LOGICAL-c526t-b58712c12b8267aff429c2410742a11328872d501d34159fad95fc6c3dc03da23</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5360247/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5360247/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28323899$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Huan, Yang W</creatorcontrib><creatorcontrib>Bengtsson, Rebecca J</creatorcontrib><creatorcontrib>MacIntyre, Neil</creatorcontrib><creatorcontrib>Guthrie, Jack</creatorcontrib><creatorcontrib>Finlayson, Heather</creatorcontrib><creatorcontrib>Smith, Sionagh H</creatorcontrib><creatorcontrib>Archibald, Alan L</creatorcontrib><creatorcontrib>Ait-Ali, Tahar</creatorcontrib><title>Lawsonia intracellularis exploits β-catenin/Wnt and Notch signalling pathways during infection of intestinal crypt to alter cell homeostasis and promote cell proliferation</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Lawsonia intracellularis is an obligate intracellular bacterial pathogen that causes proliferative enteropathy (PE) in pigs. L. intracellularis infection causes extensive intestinal crypt cell proliferation and inhibits secretory and absorptive cell differentiation. However, the affected host upstream cellular pathways leading to PE are still unknown. β-catenin/Wnt signalling is essential in maintaining intestinal stem cell (ISC) proliferation and self-renewal capacity, while Notch signalling governs differentiation of secretory and absorptive lineage specification. Therefore, in this report we used immunofluorescence (IF) and quantitative reverse transcriptase PCR (RTqPCR) to examine β-catenin/Wnt and Notch-1 signalling levels in uninfected and L. intracellularis infected pig ileums at 3, 7, 14, 21 and 28 days post challenge (dpc). We found that while the significant increase in Ki67+ nuclei in crypts at the peak of L. intracellularis infection suggested enhanced cell proliferation, the expression of c-MYC and ASCL2, promoters of cell growth and ISC proliferation respectively, was down-regulated. Peak infection also coincided with enhanced cytosolic and membrane-associated β-catenin staining and induction of AXIN2 and SOX9 transcripts, both encoding negative regulators of β-catenin/Wnt signalling and suggesting a potential alteration to β-catenin/Wnt signalling levels, with differential regulation of the expression of its target genes. We found that induction of HES1 and OLFM4 and the down-regulation of ATOH1 transcript levels was consistent with the increased Notch-1 signalling in crypts at the peak of infection. Interestingly, the significant down-regulation of ATOH1 transcript levels coincided with the depletion of MUC2 expression at 14 dpc, consistent with the role of ATOH1 in promoting goblet cell maturation. The lack of significant change to LGR5 transcript levels at the peak of infection suggested that the crypt hyperplasia was not due to the expansion of ISC population. Overall, simultaneous induction of Notch-1 signalling and the attenuation of β-catenin/Wnt pathway appear to be associated with the inhibition of goblet cell maturation and enhanced crypt cell proliferation at the peak of L. intracellularis infection. Moreover, the apparent differential regulation of apoptosis between crypt and lumen cells together with the strong induction of Notch-1 signalling and the enhanced SOX9 expression along crypts 14 dpc suggest an expansion of actively dividing transit amplifying and/or absorptive progenitor cells and provide a potential basis for understanding the development and maintenance of PE.</description><subject>Absorptivity</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Apoptosis - physiology</subject><subject>Bacteria</subject><subject>Bacterial infections</subject><subject>beta Catenin - metabolism</subject><subject>Biology and Life Sciences</subject><subject>c-Myc protein</subject><subject>Cancer</subject><subject>Caspase 3 - metabolism</subject><subject>Cell cycle</subject><subject>Cell differentiation</subject><subject>Cell division</subject><subject>Cell growth</subject><subject>Cell proliferation</subject><subject>Cell Proliferation - physiology</subject><subject>Cell self-renewal</subject><subject>Cells (biology)</subject><subject>Crypts</subject><subject>Desulfovibrionaceae Infections - metabolism</subject><subject>Desulfovibrionaceae Infections - pathology</subject><subject>Diarrhea</subject><subject>Differentiation (biology)</subject><subject>Disease Progression</subject><subject>Female</subject><subject>Gamma rays</subject><subject>Gastroenterology</subject><subject>Gene expression</subject><subject>Homeostasis</subject><subject>Homeostasis - physiology</subject><subject>Hyperplasia</subject><subject>Ileum - metabolism</subject><subject>Ileum - microbiology</subject><subject>Ileum - pathology</subject><subject>Immunofluorescence</subject><subject>Infections</subject><subject>Intestine</subject><subject>Lawsonia</subject><subject>Lawsonia Bacteria</subject><subject>Ligands</subject><subject>Male</subject><subject>Math1 protein</subject><subject>Maturation</subject><subject>Medicine and Health Sciences</subject><subject>Mucin-2 - metabolism</subject><subject>Myc protein</subject><subject>Notch protein</subject><subject>Notch1 protein</subject><subject>Nuclei</subject><subject>Progenitor cells</subject><subject>Random Allocation</subject><subject>Receptors, Notch - metabolism</subject><subject>Research and analysis methods</subject><subject>RNA-directed DNA polymerase</subject><subject>Salmonella</subject><subject>Signal transduction</subject><subject>Signaling</subject><subject>Small intestine</subject><subject>Sox9 protein</subject><subject>SOX9 Transcription Factor - metabolism</subject><subject>Stem cells</subject><subject>Studies</subject><subject>Sus scrofa</subject><subject>Transcription</subject><subject>Wnt protein</subject><subject>Wnt Signaling Pathway - physiology</subject><subject>β-Catenin</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNptUstuFDEQHCEQCYE_QGCJC5fZ-DVjzwUpinhEWsEFxNHq9Xh2vfLag-0h7D9x4kP4JjzsJkoQJ9vd1dXV5a6q5wQvCBPkfBum6MEtxuDNAhPBhKQPqlPSMVq3FLOHd-4n1ZOUthg3TLbt4-qESkaZ7LrT6ucSrlPwFpD1OYI2zk0Ook3I_BhdsDmh379qDdl468-_-ozA9-hjyHqDkl0XAc76NRohb65hn1A_xflt_WB0tsGjMMzMJmVbsEjH_ZhRDghcNhHN7dAm7ExIGVJpOpOPMexCNodkeTg7mAgz2dPq0QAumWfH86z68u7t58sP9fLT-6vLi2WtG9rmetVIQagmdCVpK2AYOO005QQLToEQRqUUtG8w6RknTTdA3zWDbjXrNWY9UHZWvTzwFgeSOhqdFJGiazFtcFcQVwdEH2Crxmh3EPcqgFV_AyGuFcRstTNKYGlIqRGMEC45XXEgfTuUSJHIV1C43hy7Taud6bWZP8LdI72f8Xaj1uG7alhRw0UheH0kiOHbVKxWO5tm98CbMM26JcaywS0v0Ff_QP8_HT-gdAwpRTPciiFYzct3U6Xm5VPH5StlL-4Oclt0s23sD_ux3LU</recordid><startdate>20170321</startdate><enddate>20170321</enddate><creator>Huan, Yang W</creator><creator>Bengtsson, Rebecca J</creator><creator>MacIntyre, Neil</creator><creator>Guthrie, Jack</creator><creator>Finlayson, Heather</creator><creator>Smith, Sionagh H</creator><creator>Archibald, Alan L</creator><creator>Ait-Ali, Tahar</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20170321</creationdate><title>Lawsonia intracellularis exploits β-catenin/Wnt and Notch signalling pathways during infection of intestinal crypt to alter cell homeostasis and promote cell proliferation</title><author>Huan, Yang W ; Bengtsson, Rebecca J ; MacIntyre, Neil ; Guthrie, Jack ; Finlayson, Heather ; Smith, Sionagh H ; Archibald, Alan L ; Ait-Ali, Tahar</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c526t-b58712c12b8267aff429c2410742a11328872d501d34159fad95fc6c3dc03da23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Absorptivity</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Apoptosis - 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pathology</topic><topic>Immunofluorescence</topic><topic>Infections</topic><topic>Intestine</topic><topic>Lawsonia</topic><topic>Lawsonia Bacteria</topic><topic>Ligands</topic><topic>Male</topic><topic>Math1 protein</topic><topic>Maturation</topic><topic>Medicine and Health Sciences</topic><topic>Mucin-2 - metabolism</topic><topic>Myc protein</topic><topic>Notch protein</topic><topic>Notch1 protein</topic><topic>Nuclei</topic><topic>Progenitor cells</topic><topic>Random Allocation</topic><topic>Receptors, Notch - metabolism</topic><topic>Research and analysis methods</topic><topic>RNA-directed DNA polymerase</topic><topic>Salmonella</topic><topic>Signal transduction</topic><topic>Signaling</topic><topic>Small intestine</topic><topic>Sox9 protein</topic><topic>SOX9 Transcription Factor - metabolism</topic><topic>Stem cells</topic><topic>Studies</topic><topic>Sus scrofa</topic><topic>Transcription</topic><topic>Wnt protein</topic><topic>Wnt Signaling Pathway - physiology</topic><topic>β-Catenin</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Huan, Yang W</creatorcontrib><creatorcontrib>Bengtsson, Rebecca J</creatorcontrib><creatorcontrib>MacIntyre, Neil</creatorcontrib><creatorcontrib>Guthrie, Jack</creatorcontrib><creatorcontrib>Finlayson, Heather</creatorcontrib><creatorcontrib>Smith, Sionagh H</creatorcontrib><creatorcontrib>Archibald, Alan L</creatorcontrib><creatorcontrib>Ait-Ali, Tahar</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Huan, Yang W</au><au>Bengtsson, Rebecca J</au><au>MacIntyre, Neil</au><au>Guthrie, Jack</au><au>Finlayson, Heather</au><au>Smith, Sionagh H</au><au>Archibald, Alan L</au><au>Ait-Ali, Tahar</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Lawsonia intracellularis exploits β-catenin/Wnt and Notch signalling pathways during infection of intestinal crypt to alter cell homeostasis and promote cell proliferation</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2017-03-21</date><risdate>2017</risdate><volume>12</volume><issue>3</issue><spage>e0173782</spage><epage>e0173782</epage><pages>e0173782-e0173782</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Lawsonia intracellularis is an obligate intracellular bacterial pathogen that causes proliferative enteropathy (PE) in pigs. L. intracellularis infection causes extensive intestinal crypt cell proliferation and inhibits secretory and absorptive cell differentiation. However, the affected host upstream cellular pathways leading to PE are still unknown. β-catenin/Wnt signalling is essential in maintaining intestinal stem cell (ISC) proliferation and self-renewal capacity, while Notch signalling governs differentiation of secretory and absorptive lineage specification. Therefore, in this report we used immunofluorescence (IF) and quantitative reverse transcriptase PCR (RTqPCR) to examine β-catenin/Wnt and Notch-1 signalling levels in uninfected and L. intracellularis infected pig ileums at 3, 7, 14, 21 and 28 days post challenge (dpc). We found that while the significant increase in Ki67+ nuclei in crypts at the peak of L. intracellularis infection suggested enhanced cell proliferation, the expression of c-MYC and ASCL2, promoters of cell growth and ISC proliferation respectively, was down-regulated. Peak infection also coincided with enhanced cytosolic and membrane-associated β-catenin staining and induction of AXIN2 and SOX9 transcripts, both encoding negative regulators of β-catenin/Wnt signalling and suggesting a potential alteration to β-catenin/Wnt signalling levels, with differential regulation of the expression of its target genes. We found that induction of HES1 and OLFM4 and the down-regulation of ATOH1 transcript levels was consistent with the increased Notch-1 signalling in crypts at the peak of infection. Interestingly, the significant down-regulation of ATOH1 transcript levels coincided with the depletion of MUC2 expression at 14 dpc, consistent with the role of ATOH1 in promoting goblet cell maturation. The lack of significant change to LGR5 transcript levels at the peak of infection suggested that the crypt hyperplasia was not due to the expansion of ISC population. Overall, simultaneous induction of Notch-1 signalling and the attenuation of β-catenin/Wnt pathway appear to be associated with the inhibition of goblet cell maturation and enhanced crypt cell proliferation at the peak of L. intracellularis infection. Moreover, the apparent differential regulation of apoptosis between crypt and lumen cells together with the strong induction of Notch-1 signalling and the enhanced SOX9 expression along crypts 14 dpc suggest an expansion of actively dividing transit amplifying and/or absorptive progenitor cells and provide a potential basis for understanding the development and maintenance of PE.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>28323899</pmid><doi>10.1371/journal.pone.0173782</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2017-03, Vol.12 (3), p.e0173782-e0173782 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1879602509 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Absorptivity Animals Apoptosis Apoptosis - physiology Bacteria Bacterial infections beta Catenin - metabolism Biology and Life Sciences c-Myc protein Cancer Caspase 3 - metabolism Cell cycle Cell differentiation Cell division Cell growth Cell proliferation Cell Proliferation - physiology Cell self-renewal Cells (biology) Crypts Desulfovibrionaceae Infections - metabolism Desulfovibrionaceae Infections - pathology Diarrhea Differentiation (biology) Disease Progression Female Gamma rays Gastroenterology Gene expression Homeostasis Homeostasis - physiology Hyperplasia Ileum - metabolism Ileum - microbiology Ileum - pathology Immunofluorescence Infections Intestine Lawsonia Lawsonia Bacteria Ligands Male Math1 protein Maturation Medicine and Health Sciences Mucin-2 - metabolism Myc protein Notch protein Notch1 protein Nuclei Progenitor cells Random Allocation Receptors, Notch - metabolism Research and analysis methods RNA-directed DNA polymerase Salmonella Signal transduction Signaling Small intestine Sox9 protein SOX9 Transcription Factor - metabolism Stem cells Studies Sus scrofa Transcription Wnt protein Wnt Signaling Pathway - physiology β-Catenin |
| title | Lawsonia intracellularis exploits β-catenin/Wnt and Notch signalling pathways during infection of intestinal crypt to alter cell homeostasis and promote cell proliferation |
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