PTPN2 Dysfunction Exacerbates C. rodentium Infection and Prevents Bacterial Clearance in a Cell‐Type Specific Manner
Authors: Spalinger Marianne Rebecca , Sayoc Anica , Santos Alina N. , Shawki Ali , Krishnan Moorthy , Li Jiang , Scharl M , Hanson E , Eckmann Lars , Nair Meera G. , McCole Declan F. 
Published: April 2020

Background/AimLoss‐of‐function variants within the gene locus encoding protein tyrosine phosphatase non‐receptor type 2 (PTPN2) are linked with increased susceptibility to inflammatory diseases, including gastrointestinal disorders such as inflammatory bowel disease. Deletion of PTPN2 in myeloid cells promotes susceptibility to experimental colitis, and its loss in intestinal epithelial cells results in intestinal barrier defects, but it is not known how this affects susceptibility to bacterial infections. The aim of this project was to investigate the role of PTPN2 during infection with enteropathogenic bacteria.Methods8–12 week old, male and female mice (i) constitutively heterozygous for PTPN2 (PTPN2‐Het mice), (ii) lacking PTPN2 specifically in myeloid immune cells (PTPN2‐LysMCre mice), or (iii) with tamoxifen‐induced deletion in intestinal epithelial cells (PTPN2‐VilCre mice) and their respective wild‐type (WT) littermates were infected with Citrobacter rodentium (C. rodentium) and disease monitored over 21 days.ResultsWT mice suffered from moderate disease activity (moderate diarrhea and weight loss, reduced activity/grooming) upon infection with C. rodentium and recovered from disease by day 20. PTPN2‐Het mice showed significantly enhanced disease activity (pronounced weight loss (p<0.01), severe diarrhea, reduced activity and lack of grooming), enhanced C. rodentium load in feces and translocation (p<0.01, each) and were not able to clear infection. In contrast, PTPN2‐LysMCre mice showed severe early‐onset disease (drastic weight loss (p<0.05), severe diarrhea, reduced activity and lack of grooming) and clearly enhanced C. rodentium fecal load and translocation (p<0.01, each) between day 5 and 10 of the infection, but recovered faster from disease (p<0.05) and completely cleared the infection by day 16. PTPN2‐VilCre mice showed more severe disease than floxed control mice (p<0.05), but were able to recover/clear the infection by day 21. PTPN2‐LysMCre and PTPN2‐Het, but not PTPN2‐VilCre mice, mounted a more pronounced type 1 immune response (increased numbers of pro‐inflammatory macrophages and T helper (Th)1 and Th17 cells, p<0.05, each) and enhanced IL‐22 expression (LysMCre: p<0.05; Het: p<0.01). Furthermore, C. rodentium infection induced expression of anti‐microbial peptides in IECs from WT mice, an effect potentiated in PTPN2‐LysMCre mice, which might account for the faster bacterial clearance/recovery. In contrast, IECs from PTPN2‐Het and PTPN2VilCre mice were unable to upregulate anti‐microbial peptides.ConclusionPTPN2 protects from bacterial infections by restricting worsens disease burden and defects in bacterial clearance. This highlights the importance of PTPN2 for intestinal health and might partially explain the increased disease risk in individuals carrying PTPN2 variants with respect to host responses to bacterial triggers of inflammatory disease.Support or Funding InformationNIH 2R01DK091281 to DFM and a Postdoctoral Fellowship from the Swiss National Science Foundation to MRS.