| Autor: |
Kao, Daniel J., Saeedi, Bejan J., Kitzenberg, David, Burney, Krista M., Dobrinskikh, Evgenia, Battista, Kayla D., Vázquez-Torres, Andrés, Colgan, Sean P., Kominsky, Douglas J. |
| Zdroj: |
Infection and Immunity; July 2017, Vol. 85 Issue: 10 |
| Abstrakt: |
ABSTRACTEcto-5′-nucleotidase (CD73) is expressed abundantly on the apical surface of intestinal epithelial cells (IECs) and functions as the terminal enzyme in the generation of extracellular adenosine. Previous work demonstrated that adenosine signaling in IECs results in a number of tissue-protective effects during inflammation; however, a rationale for its apical expression has been lacking. We hypothesized that the highly polarized expression of CD73 is indicative of an important role for extracellular adenosine as a mediator of host-microbe interactions. We show that adenosine harbors bacteriostatic activity against Salmonella entericaserovar Typhimurium that is not shared by the related purine metabolite 5′-AMP, inosine, or hypoxanthine. Analysis of Salmonellacolonization in IEC-specific CD73 knockout mice (CD73f/fVillinCre) revealed a nearly 10-fold increase in colonization compared to that in controls. Despite the increased luminal colonization by Salmonella, CD73f/fVillinCremice were protected against Salmonellacolitis and showed reduced Salmonellaburdens in viscera, suggesting that adenosine promotes dissemination. The knockdown of CD73 expression in cultured IECs resulted in dramatic defects in intraepithelial localization and replication as well as defective transepithelial translocation by Salmonella. In conclusion, we define a novel antimicrobial activity of adenosine in the gastrointestinal tract and unveil an important role for adenosine as a regulator of host-microbe interactions. These findings have broad implications for the development of new therapeutic agents for infectious disease. |
| Databáze: |
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