The Mucin Muc2 Limits Pathogen Burdens and Epithelial Barrier Dysfunction during Salmonella enterica Serovar Typhimurium Colitis
Open accessAbstract
Salmonella enterica serovar Typhimurium is a model organism used to explore the virulence strategies underlying Salmonella pathogenesis. Although intestinal mucus is the first line of defense in the intestine, its role in protection against Salmonella is still unclear. The intestinal mucus layer is composed primarily of the Muc2 mucin, a heavily O-glycosylated glycoprotein. The core 3-derived O-glycans of Muc2 are synthesized by core 3 β1,3- N -acetylglucosaminyltransferase (C3GnT). Mice lacking these glycans still produce Muc2 but display a thinner intestinal mucus barrier. We began our investigations by comparing Salmonella -induced colitis and mucus dynamics in Muc2 -deficient ( Muc2 −/− ) mice, C3GnT −/− mice, and wild-type C57BL/6 (WT) mice. Salmonella infection led to increases in luminal Muc2 secretion in WT and C3GnT −/− mice. When Muc2 −/− mice were infected with Salmonella , they showed dramatic susceptibility to infection, carrying significantly higher cecal and liver pathogen burdens, and developing significantly higher barrier disruption and higher mortality rates, than WT mice. We found that the exaggerated barrier disruption in infected Muc2 −/− mice was invA dependent. We also tested the susceptibility of C3GnT −/− mice and found that they carried pathogen burdens similar to those of WT mice but developed exaggerated barrier disruption. Moreover, we found that Muc2 −/− mice were impaired in intestinal alkaline phosphatase (IAP) expression and lipopolysaccharide (LPS) detoxification activity in their ceca, potentially explaining their high mortality rates during infection. Our data suggest that the intestinal mucus layer (Muc2) and core 3 O-glycosylation play critical roles in controlling Salmonella intestinal burdens and intestinal epithelial barrier function, respectively.
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Pathogenic bacteria can be expected to have capacities to destroy mucus because they have developed specific mechanisms to circumvent the mucus protective system.
“Such capacities can be expected among pathogenic bacteria as these have developed specific mechanisms to circumvent the mucus protective system 36, 37, 38.”
From The composition of the gut microbiota shapes the colon mucus barrier (2015) · cites this paper as [38]
Cites
Van der Sluis, M., De Koning, B. A. E., De Bruijn, A. C. J. M., Velcich, A., Meijerink, J. P. P., Van Goudoever, J. B., Büller, H. A., Dekker, J., Van Seuningen, I., Renes, I. B., et al. (2006) · Gastroenterology · doi:10.1053/j.gastro.2006.04.020 · Cited by 1,684 · see citing works
Self-citationJohansson, M., Larsson, J. M. H., & Hansson, G. C. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1006451107 · Cited by 1,459 · see citing works
Intestinal Goblet Cells and Mucins in Health and Disease: Recent Insights and Progress
Kim, Y. S., & Ho, S. B. (2010) · Current Gastroenterology Reports · doi:10.1007/s11894-010-0131-2 · Cited by 1,437 · see citing works
Mucin dynamics and enteric pathogens
McGuckin, M. A., Lindén, S. K., Sutton, P., & Florin, T. H. (2011) · Nature Reviews Microbiology · doi:10.1038/nrmicro2538 · Cited by 1,428 · see citing works
The indigenous gastrointestinal microflora
Berg, R. (1996) · Trends in Microbiology · doi:10.1016/0966-842x(96)10057-3 · Cited by 1,153 · see citing works
Barthel, M., Hapfelmeier, S., Quintanilla-Martínez, L., Kremer, M., Rohde, M., Hogardt, M., Pfeffer, K., Rüssmann, H., & Hardt, W.-D. (2003) · Infection and Immunity · doi:10.1128/iai.71.5.2839-2858.2003 · Cited by 1,020 · see citing works
Galán, J. E., & Curtiss, R. (1989) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.86.16.6383 · Cited by 990 · see citing works
Baykov, A. A., Evtushenko, O. A., & Avaeva, S. M. (1988) · Analytical Biochemistry · doi:10.1016/0003-2697(88)90484-8 · Cited by 790 · see citing works
Bates, J. M., Akerlund, J., Mittge, E., & Guillemin, K. J. (2007) · Cell Host & Microbe · doi:10.1016/j.chom.2007.10.010 · Cited by 752 · see citing works
Bergstrom, K. S. B., Kissoon-Singh, V., Gibson, D. L., Ma, C., Montero, M., Sham, H. P., Ryz, N., Huang, T., Velcich, A., Finlay, B. B., et al. (2010) · PLoS Pathogens · doi:10.1371/journal.ppat.1000902 · Cited by 625 · see citing works
Self-citationVidal, S., Tremblay, M. L., Govoni, G., Gauthier, S., Sebastiani, G., Malo, D., Skamene, E., Olivier, M., Jothy, S., & Gros, P. (1995) · The Journal of experimental medicine · doi:10.1084/jem.182.3.655 · Cited by 603 · see citing works
Galán, J. E., Ginocchio, C. C., & Costeas, P. (1992) · Journal of Bacteriology · doi:10.1128/jb.174.13.4338-4349.1992 · Cited by 584 · see citing works
Salmonella: A Model for Bacterial Pathogenesis
Ohl, M., & Miller, S. I. (2001) · Annual Review of Medicine · doi:10.1146/annurev.med.52.1.259 · Cited by 476 · see citing works
Animal models of infections: enteritis versus typhoid fever
Santos, R. L., Zhang, S., Tsolis, R. M., Kingsley, R. A., Adams, L. G., & Bäumler, A. J. (2001) · Microbes and Infection · doi:10.1016/s1286-4579(01)01495-2 · Cited by 450 · see citing works
MUC1 cell surface mucin is a critical element of the mucosal barrier to infection
McAuley, J., Lindén, S. K., Png, C. W., King, R. M., Pennington, H. L., Gendler, S. J., Florin, T. H., Hill, G. R., Korolik, V., & McGuckin, M. A. (2007) · Journal of Clinical Investigation · doi:10.1172/jci26705 · Cited by 437 · see citing works
Hess, J., Ladel, C. H., Miko, D., & Kaufmann, S. H. E. (1996) · The Journal of Immunology · doi:10.4049/jimmunol.156.9.3321 · Cited by 394 · see citing works
Intestinal alkaline phosphatase is a gut mucosal defense factor maintained by enteral nutrition
Goldberg, R. F., Austen, W., Zhang, X.-B., Munene, G., Mostafa, G., Biswas, S., McCormack, M., Eberlin, K., Nguyen, J. T., Tatlıdede, H. S., et al. (2008) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.0712140105 · Cited by 381 · see citing works
Lallès, J. P. (2010) · Nutrition Reviews · doi:10.1111/j.1753-4887.2010.00292.x · Cited by 366 · see citing works
Larsson, J. M. H., Karlsson, H., Crespo, J. G., Johansson, M., Eklund, L., Sjövall, H., & Hansson, G. C. (2011) · Inflammatory Bowel Diseases · doi:10.1002/ibd.21625 · Cited by 361 · see citing works
Increased susceptibility to colitis and colorectal tumors in mice lacking core 3–derived O-glycans
An, G., Wei, B., Xia, B., McDaniel, J. M., Ju, T., Cummings, R. D., Braun, J., & Xia, L. (2007) · The Journal of Experimental Medicine · doi:10.1084/jem.20061929 · Cited by 352 · see citing works
Self-citationSalmonella Interactions with Polarized Human Intestinal Caco-2 Epithelial Cells
Finlay, B. B., & Falkow, S. (1990) · The Journal of Infectious Diseases · doi:10.1093/infdis/162.5.1096 · Cited by 320 · see citing works
Larsson, J. M. H., Karlsson, H., Sjövall, H., & Hansson, G. C. (2009) · Glycobiology · doi:10.1093/glycob/cwp048 · Cited by 282 · see citing works
Mucin Dynamics in Intestinal Bacterial Infection
Lindén, S. K., Florin, T. H., & McGuckin, M. A. (2008) · PLoS ONE · doi:10.1371/journal.pone.0003952 · Cited by 235 · see citing works
Ghosh, S., DeCoffe, D., Brown, K., Rajendiran, E., Estaki, M., Dai, C., Yip, A., & Gibson, D. L. (2013) · PLoS ONE · doi:10.1371/journal.pone.0055468 · Cited by 214 · see citing works
Removal of Phosphate from Lipid A as a Strategy to Detoxify Lipopolysaccharide
Bentala, H., Verweij, W. R., der Vlag, A. H., et al. (2002) · Shock · doi:10.1097/00024382-200212000-00013 · Cited by 209 · see citing works
Boyle, E. C., Brown, N. F., & Finlay, B. B. (2006) · Cellular Microbiology · doi:10.1111/j.1462-5822.2006.00762.x · Cited by 208 · see citing works
Beumer, C., Wulferink, M., Raaben, W., et al. (2003) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.103.056606 · Cited by 179 · see citing works
Dephosphorylation of endotoxin by alkaline phosphatase in vivo.
Poelstra, K., Bakker, W. W., Klok, P. A., et al. (1997) · PubMed · Cited by 176 · see citing works
Iwai, T., Inaba, N., Naundorf, A., Zhang, Y., Gotoh, M., Iwasaki, H., Kudo, T., Togayachi, A., Ishizuka, Y., Nakanishi, H., et al. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m112457200 · Cited by 176 · see citing works
Vazquez-Torres, A., Vallance, B. A., Bergman, M. A., Finlay, B. B., Cookson, B. T., Jones-Carson, J., & Fang, F. C. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.172.10.6202 · Cited by 173 · see citing works
Self-citationCoombes, B. K., Coburn, B. A., Potter, A. A., Gomis, S. M., Mirakhur, K. K., Li, Y., & Finlay, B. B. (2005) · Infection and Immunity · doi:10.1128/iai.73.11.7161-7169.2005 · Cited by 168 · see citing works
A physiologic function for alkaline phosphatase: endotoxin detoxification.
Poelstra, K., Bakker, W. W., Klok, P. A., et al. (1997) · PubMed · Cited by 159 · see citing works
Chatfield, S. N., Strahan, K. M., Pickard, D., Charles, I. G., Hormaeche, C. E., & Gordon Dougan, B. (1992) · Microbial Pathogenesis · doi:10.1016/0882-4010(92)90117-7 · Cited by 153 · see citing works
TLR4 signalling in the intestine in health and disease
Fukata, M., & Abreu, M. T. (2007) · Biochemical Society Transactions · doi:10.1042/bst0351473 · Cited by 142 · see citing works
Muc1 mucins on the cell surface are adhesion sites forPseudomonas aeruginosa
Lillehoj, E. P., Hyun, S. W., Kim, B. T., et al. (2001) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.2001.280.1.l181 · Cited by 121 · see citing works
Periodic acid — Schiff — Alcian Blue: A method for the differential staining of glycoproteins
Yamabayashi, S. (1987) · The Histochemical Journal · doi:10.1007/bf01687364 · Cited by 119 · see citing works
Yrlid, U., Svensson, M., Håkansson, A., Chambers, B. J., Ljunggren, H., & Wick, M. J. (2001) · Infection and Immunity · doi:10.1128/iai.69.9.5726-5735.2001 · Cited by 115 · see citing works
Tu, Q. V., McGuckin, M. A., & Mendz, G. L. (2008) · Journal of Medical Microbiology · doi:10.1099/jmm.0.47752-0 · Cited by 112 · see citing works
Menéndez, A., Arena, E. T., Guttman, J. A., Thorson, L., Vallance, B. A., Vogl, A. W., & Finlay, B. B. (2009) · The Journal of Infectious Diseases · doi:10.1086/646608 · Cited by 105 · see citing works
Self-citationJepson, M. A., Collares‐Buzato, C. B., Clark, M. A., Hirst, B. H., & Simmons, N. L. (1995) · Infection and Immunity · doi:10.1128/iai.63.1.356-359.1995 · Cited by 102 · see citing works
Yang, K., Popova, N. V., Yang, W., Lozonschi, I., Tadesse, S., Kent, S., Bancroft, L. K., Matise, I., Cormier, R. T., Scherer, S. J., et al. (2008) · Cancer Research · doi:10.1158/0008-5472.can-08-0598 · Cited by 96 · see citing works
Self-citationBinding of Yersinia enterocolitica to rabbit intestinal brush border membranes, mucus, and mucin
Mantle, M., Basaraba, L., Peacock, S. C., & Gall, D. (1989) · Infection and Immunity · doi:10.1128/iai.57.11.3292-3299.1989 · Cited by 93 · see citing works
Mucin Degradation Mechanisms by DistinctPseudomonas aeruginosaIsolates In Vitro
Aristoteli, L. P., & Willcox, M. D. P. (2003) · Infection and Immunity · doi:10.1128/iai.71.10.5565-5575.2003 · Cited by 78 · see citing works
Lectins and also bacteria modify the glycosylation of gut surface receptors in the rat
Pusztai, A. J., Ewen, S. W. B., Grant, G., Peumans, W. J., Damme, E. J. M. V., Coates, M. E., & Bardócz, S. (1995) · Glycoconjugate Journal · doi:10.1007/bf00731865 · Cited by 74 · see citing works
van Veen, S. Q., van Vliet, A. K., Wulferink, M., et al. (2005) · Infection and Immunity · doi:10.1128/iai.73.7.4309-4314.2005 · Cited by 67 · see citing works
Jepson, M. A., Schlecht, H., & Collares‐Buzato, C. B. (2000) · Infection and Immunity · doi:10.1128/iai.68.12.7202-7208.2000 · Cited by 50 · see citing works
Holmén, J. M., Olson, F. J., Karlsson, H., et al. (2002) · Glycoconjugate Journal · doi:10.1023/a:1022589015687 · Cited by 39 · see citing works
Kalupahana, R. S., Mastroeni, P., Maskell, D. J., & Blacklaws, B. (2005) · Immunology · doi:10.1111/j.1365-2567.2005.02180.x · Cited by 37 · see citing works
Epithelial inflammation response induced by Shigella flexneri depends on mucin gene expression
Nutten, S., Sansonetti, P. J., Huet, G., et al. (2002) · Microbes and Infection · doi:10.1016/s1286-4579(02)01636-2 · Cited by 36 · see citing works
Binding of Shigella to rat and human intestinal mucin
Rajkumar, R., Devaraj, H., & Niranjali, S. (1998) · Molecular and Cellular Biochemistry · doi:10.1023/a:1006844125976 · Cited by 24 · see citing works
Månsson, L., Montero, M., Zarepour, M., Bergstrom, K., Ma, C., Huang, T., Man, C., Graßl, G. A., & Vallance, B. A. (2012) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00038.2012 · Cited by 24 · see citing works
Self-citationMasselot, C. R., Herrmann, A., Carlstedt, I., et al. (2007) · Glycoconjugate Journal · doi:10.1007/s10719-007-9079-3 · Cited by 19 · see citing works
Özkaya, H., Akcan, A. B., Aydemir, G., Aydınöz, S., Razia, Y., Gammon, S. T., & McKinney, J. S. (2012) · PubMed · Cited by 18 · see citing works
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Pickard, J. M., Zeng, M. Y., Caruso, R., & Núñez, G. (2017) · Immunological Reviews · doi:10.1111/imr.12567 · Cited by 1,699 · see citing works
Pelaseyed, T., Bergström, J. H., Gustafsson, J. K., Ermund, A., Birchenough, G. M. H., Schütte, A., van der Post, S., Svensson, F., Rodríguez‐Piñeiro, A. M., Nyström, E. E. L., et al. (2014) · Immunological Reviews · doi:10.1111/imr.12182 · Cited by 1,363 · see citing works
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Allaire, J. M., Crowley, S. M., Law, H. T., Chang, S.-Y., Ko, H.-J., & Vallance, B. A. (2018) · Trends in Immunology · doi:10.1016/j.it.2018.04.002 · Cited by 933 · see citing works
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“Such capacities can be expected among pathogenic bacteria as these have developed specific mechanisms to circumvent the mucus protective system [36–38].”
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Ducarmon, Q. R., Zwittink, R. D., Hornung, B. V. H., van Schaik, W., Young, V. B., & Kuijper, E. J. (2019) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.00007-19 · Cited by 566 · see citing works
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Li, H., Limenitakis, J. P., Fuhrer, T., Geuking, M. B., Lawson, M. A., Wyss, M., Brugiroux, S., Keller, I., Macpherson, J. A., Rupp, S., et al. (2015) · Nature Communications · doi:10.1038/ncomms9292 · Cited by 511 · see citing works
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Self-citation
- Authors
- Zarepour, M., Bhullar, K., Montero, M., Ma, C., Huang, T., Velcich, A., Xia, L., & Vallance, B. A.
- Affiliations
- Child and Family Research Institute (CA)
- Albert Einstein College of Medicine (US)
- Oklahoma Medical Research Foundation (US)
- Venue
- Infection and Immunity
- Publisher
- American Society for Microbiology
- Published
- 2013-10
- Volume
- 81
- Issue
- 10
- Pages
- 3672-3683
- ISSN
- 0019-9567 (ISSN-L)
- 1098-5522
- PMC
- PMC3811786
- OpenAlex
- W2106362526
- Cited by
- 206
- References
- 53
- Citations by year
- 2026: 4 · 2025: 15 · 2024: 15 · 2023: 21 · 2022: 21 · 2021: 20 · 2020: 21 · 2019: 25 · 2018: 12 · 2017: 14 · 2016: 6 · 2015: 21 · 2014: 10
- FWCI
- 18.24
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Infection and Immunity (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK085691)
- Topics
- Life Sciences › Agricultural and Biological Sciences › Food Science › Salmonella and Campylobacter epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Escherichia coli research studies
- Keywords
- MUC2, Salmonella typhimurium, intestinal mucus barrier, invA gene, intestinal alkaline phosphatase, lipopolysaccharide detoxification, epithelial barrier dysfunction, pathogen burden, host susceptibility to infection
- MeSH terms
- Animals, Colitis, Gene Expression Regulation, Intestinal Mucosa, Lipopolysaccharides, Mice, Inbred C57BL, Polysaccharides, Salmonella Infections, Animal, Salmonella typhimurium, Mice, Knockout, Mice, Mucin-2
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