Skip to main content
Log in

Pten gene deletion in intestinal epithelial cells enhances susceptibility to Salmonella Typhimurium infection in mice

  • Microbial Pathogenesis and Host-Microbe Interaction
  • Published:
Journal of Microbiology Aims and scope Submit manuscript

Abstract

Although phosphatase and tensin homolog (PTEN) is typically considered a tumor-suppressor gene, it was recently suggested that PTEN regulates TLR5-induced immune and inflammatory responses in intestinal epithelial cells (IECs), suggesting an immunomodulatory function of PTEN in the gut. However, this alternative function of PTEN has not yet been evaluated in an in vivo context of protection against enteropathogenic bacteria. To address this, we utilized IEC-restricted Pten knockout (PtenΔIEC/ΔIEC) and littermate Pten+/+ mice. These mice were subjected to the streptomycin-pre-treated mouse model of Salmonella infection, and subsequently given an oral gavage of a low inoculum (2 × 104 CFU) of Salmonella enterica serovar Typhimurium (S. Typhimurium). This bacterial infection not only increased the mortality of PtenΔIEC/ΔIEC mice compared to Pten+/+ mice, but also induced deleterious gastrointestinal inflammation in PtenΔIEC/ΔIEC mice manifested by massive histological damage to the intestinal mucosa. S. Typhimurium infection up-regulated pro-inflammatory cytokine production in the intestine of PtenΔIEC/ΔIEC mice compared to controls. Furthermore, bacterial loads were greatly increased in the liver, mesenteric lymph node, and spleen of PtenΔIEC/ΔIEC mice compared to controls. Together, these results suggest that IEC-restricted Pten deficiency renders the host greatly susceptible to Salmonella infection and support an immune-regulatory role of PTEN in the gut.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  • Altmeyer, M., Barthel, M., Eberhard, M., Rehrauer, H., Hardt, W.D., and Hottiger, M.O. 2010. Absence of poly(ADP-ribose) polymerase 1 delays the onset of Salmonella enterica serovar Typhimurium-induced gut inflammation. Infect. Immun. 78, 3420–3431.

    Article  CAS  Google Scholar 

  • Barthel, M., Hapfelmeier, S., Quintanilla-Martinez, L., Kremer, M., Rohde, M., Hogardt, M., Pfeffer, K., Russmann, H., and Hardt, W.D. 2003. Pretreatment of mice with streptomycin provides a Salmonella enterica serovar Typhimurium colitis model that allows analysis of both pathogen and host. Infect. Immun. 71, 2839–2858.

    Article  CAS  Google Scholar 

  • Bravo-Blas, A., Utriainen, L., Clay, S.L., Kastele, V., Cerovic, V., Cunningham, A.F., Henderson, I.R., Wall, D.M., and Milling, S.W.F. 2019. Salmonella enterica serovar Typhimurium travels to mesenteric lymph nodes both with host cells and autonomously. J. Immunol. 202, 260–267.

    Article  CAS  Google Scholar 

  • Cao, X., Wei, G., Fang, H., Guo, J., Weinstein, M., Marsh, C.B., Ostrowski, M.C., and Tridandapani, S. 2004. The inositol 3-phosphatase PTEN negatively regulates Fcγ receptor signaling, but supports toll-like receptor 4 signaling in murine peritoneal macrophages. J. Immunol. 172, 4851–4857.

    Article  CAS  Google Scholar 

  • Choi, Y.J., Im, E., Chung, H.K., Pothoulakis, C., and Rhee, S.H. 2010. TRIF mediates toll-like receptor 5-induced signaling in intestinal epithelial cells. J. Biol. Chem. 285, 37570–37578.

    Article  CAS  Google Scholar 

  • Choi, Y.J., Jung, J., Chung, H.K., Im, E., and Rhee, S.H. 2013. PTEN regulates TLR5-induced intestinal inflammation by controlling Mal/TIRAP recruitment. FASEB J. 27, 243–254.

    Article  CAS  Google Scholar 

  • Ellenbroek, G.H., van Puijvelde, G.H., Anas, A.A., Bot, M., Asbach, M., Schoneveld, A., van Santbrink, P.J., Foks, A.C., Timmers, L., Doevendans, P.A., et al. 2017. Leukocyte TLR5 deficiency inhibits atherosclerosis by reduced macrophage recruitment and defective T-cell responsiveness. Sci. Rep. 7, 42688.

    Article  CAS  Google Scholar 

  • Erova, T.E., Kirtley, M.L., Fitts, E.C., Ponnusamy, D., Baze, W.B., Andersson, J.A., Cong, Y., Tiner, B.L., Sha, J., and Chopra, A.K. 2016. Protective immunity elicited by oral immunization of mice with Salmonella enterica serovar Typhimurium braun lipoprotein (Lpp) and acetyltransferase (MsbB) mutants. Front. Cell. Infect. Microbiol. 6, 148.

    Article  Google Scholar 

  • Fields, P.I., Swanson, R.V., Haidaris, C.G., and Heffron, F. 1986. Mutants of Salmonella typhimurium that cannot survive within the macrophage are avirulent. Proc. Natl. Acad. Sci. USA 83, 5189–5193.

    Article  CAS  Google Scholar 

  • Govoni, G. and Gros, P. 1998. Macrophage NRAMP1 and its role in resistance to microbial infections. Inflamm. Res. 47, 277–284.

    Article  CAS  Google Scholar 

  • Groszer, M., Erickson, R., Scripture-Adams, D.D., Lesche, R., Trumpp, A., Zack, J.A., Kornblum, H.I., Liu, X., and Wu, H. 2001. Negative regulation of neural stem/progenitor cell proliferation by the Pten tumor suppressor gene in vivo. Science 294, 2186–2189.

    Article  CAS  Google Scholar 

  • Gut, A.M., Vasiljevic, T., Yeager, T., and Donkor, O.N. 2018. Salmonella infection — prevention and treatment by antibiotics and probiotic yeasts: A review. Microbiology 164, 1327–1344.

    Article  CAS  Google Scholar 

  • Haddadi, N., Lin, Y., Travis, G., Simpson, A.M., Nassif, N.T., and McGowan, E.M. 2018. PTEN/PTENP1: ‘Regulating the regulator of RTK-dependent PI3K/Akt signalling’, new targets for cancer therapy. Mol. Cancer 17, 37.

    Article  Google Scholar 

  • Hapfelmeier, S. and Hardt, W.D. 2005. A mouse model for S. typhimurium-induced enterocolitis. Trends Microbiol. 13, 497–503.

    Article  CAS  Google Scholar 

  • Howe, C., Kim, S.J., Mitchell, J., Im, E., Kim, Y.S., Kim, Y.S., and Rhee, S.H. 2018. Differential expression of tumor-associated genes and altered gut microbiome with decreased Akkermansia muciniphila confer a tumor-preventive microenvironment in intestinal epithelial pten-deficient mice. Biochim. Biophys. Acta Mol. Basis Dis. 1864, 3746–3758.

    Article  CAS  Google Scholar 

  • Hsu, F. and Mao, Y. 2015. The structure of phosphoinositide phosphatases: Insights into substrate specificity and catalysis. Biochim. Biophys. Acta 1851, 698–710.

    Article  CAS  Google Scholar 

  • Im, E., Jung, J., Pothoulakis, C., and Rhee, S.H. 2014. Disruption of Pten speeds onset and increases severity of spontaneous colitis in IL10 -/- mice. Gastroenterology 147, 667–679.e610.

    Article  Google Scholar 

  • Jamaspishvili, T., Berman, D.M., Ross, A.E., Scher, H.I., De Marzo, A.M., Squire, J.A., and Lotan, T.L. 2018. Clinical implications of PTEN loss in prostate cancer. Nat. Rev. Urol. 15, 222–234.

    Article  CAS  Google Scholar 

  • Kagan, J.C. and Medzhitov, R. 2006. Phosphoinositide-mediated adaptor recruitment controls toll-like receptor signaling. Cell 125, 943–955.

    Article  CAS  Google Scholar 

  • Kaiser, P., Diard, M., Stecher, B., and Hardt, W.D. 2012. The streptomycin mouse model for Salmonella diarrhea: Functional analysis of the microbiota, the pathogen’s virulence factors, and the host’s mucosal immune response. Immunol. Rev. 245, 56–83.

    Article  CAS  Google Scholar 

  • Langlois, M.J., Roy, S.A., Auclair, B.A., Jones, C., Boudreau, F., Carrier, J.C., Rivard, N., and Perreault, N. 2009. Epithelial phosphatase and tensin homolog regulates intestinal architecture and secretory cell commitment and acts as a modifier gene in neoplasia. FASEB J. 23, 1835–1844.

    Article  CAS  Google Scholar 

  • Liu, H., Chen, F., Wu, W., Cao, A.T., Xue, X., Yao, S., Evans-Marin, H.L., Li, Y.Q., and Cong, Y. 2016. TLR5 mediates CD172α+ intestinal lamina propria dendritic cell induction of Th17 cells. Sci. Rep. 6, 22040.

    Article  CAS  Google Scholar 

  • Madison, B.B., Dunbar, L., Qiao, X.T., Braunstein, K., Braunstein, E., and Gumucio, D.L. 2002. cis elements of the villin gene control expression in restricted domains of the vertical (crypt) and horizontal (duodenum, cecum) axes of the intestine. J. Biol. Chem. 277, 33275–33283.

    Article  CAS  Google Scholar 

  • Que, W.C., Qiu, H.Q., Cheng, Y., Liu, M.B., and Wu, C.Y. 2018. PTEN in kidney cancer: A review and meta-analysis. Clin. Chim. Acta 480, 92–98.

    Article  CAS  Google Scholar 

  • Rhee, S.H., Kim, H., Moyer, M.P., and Pothoulakis, C. 2006. Role of MyD88 in phosphatidylinositol 3-kinase activation by flagellin/toll-like receptor 5 engagement in colonic epithelial cells. J. Biol. Chem. 281, 18560–18568.

    Article  CAS  Google Scholar 

  • Rhee, S.H., Ma, E.L., Lee, Y., Tache, Y., Pothoulakis, C., and Im, E. 2015. Corticotropin releasing hormone and urocortin 3 stimulate vascular endothelial growth factor expression through the cAMP/CREB pathway. J. Biol. Chem. 290, 26194–26203.

    Article  CAS  Google Scholar 

  • Stecher, B., Paesold, G., Barthel, M., Kremer, M., Jantsch, J., Stallmach, T., Heikenwalder, M., and Hardt, W.D. 2006. Chronic Salmonella enterica serovar Typhimurium-induced colitis and cholangitis in streptomycin-pretreated Nramp1 +/+ mice. Infect. Immun. 74, 5047–5057.

    Article  CAS  Google Scholar 

  • Tsolis, R.M., Kingsley, R.A., Townsend, S.M., Ficht, T.A., Adams, L.G., and Baumler, A.J. 1999. Of mice, calves, and men. Comparison of the mouse typhoid model with other Salmonella infections. Adv. Exp. Med. Biol. 473, 261–274.

    Article  CAS  Google Scholar 

  • Vecchio, L., Seke Etet, P.F., Kipanyula, M.J., Krampera, M., and Nwabo Kamdje, A.H. 2013. Importance of epigenetic changes in cancer etiology, pathogenesis, clinical profiling, and treatment: What can be learned from hematologic malignancies? Biochim. Biophys. Acta 1836, 90–104.

    CAS  PubMed  Google Scholar 

  • Vijayan, A., Rumbo, M., Carnoy, C., and Sirard, J.C. 2018. Compartmentalized antimicrobial defenses in response to flagellin. Trends Microbiol. 26, 423–435.

    Article  CAS  Google Scholar 

  • Yu, M., Trobridge, P., Wang, Y., Kanngurn, S., Morris, S.M., Knoblaugh, S., and Grady, W.M. 2014. Inactivation of TGF-β signaling and loss of PTEN cooperate to induce colon cancer in vivo. Oncogene 33, 1538–1547.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This research was supported by grants from Oakland University and the National Institutes of Health (DK079015, S.H.R) and the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. 2019R1A2C1010536 to E.I.).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Sang Hoon Rhee.

Ethics declarations

The authors declare that they have no conflicts of interest with the contents of this article.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Howe, C., Mitchell, J., Kim, S.J. et al. Pten gene deletion in intestinal epithelial cells enhances susceptibility to Salmonella Typhimurium infection in mice. J Microbiol. 57, 1012–1018 (2019). https://doi.org/10.1007/s12275-019-9320-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12275-019-9320-3

Keywords

Navigation