Autoimmune susceptibility gene <i>PTPN2</i> is required for clearance of adherent-invasive <i>Escherichia coli</i> by integrating bacterial uptake and lysosomal defence.

Abstract

Alterations in the intestinal microbiota are linked with a wide range of autoimmune and inflammatory conditions, including inflammatory bowel diseases (IBD), where pathobionts penetrate the intestinal barrier and promote inflammatory reactions. In patients with IBD, the ability of intestinal macrophages to efficiently clear invading pathogens is compromised resulting in increased bacterial translocation and excessive immune reactions. Here, we investigated how an IBD-associated loss-of-function variant in the protein tyrosine phosphatase non-receptor type 2 (<i>PTPN2</i>) gene, or loss of PTPN2 expression affected the ability of macrophages to respond to invading bacteria. IBD patient-derived macrophages with wild-type (WT) <i>PTPN2</i> or carrying the IBD-associated <i>PTPN2</i> SNP, peritoneal macrophages from WT and constitutive PTPN2-knockout mice, as well as mice specifically lacking <i>PTPN2</i> in macrophages were infected with non-invasive K12 <i>Escherichia coli</i>, the human adherent-invasive <i>E. coli</i> (AIEC) <i>LF82</i>, or a novel mouse AIEC (<i>m</i>AIEC) strain. Loss of PTPN2 severely compromises the ability of macrophages to clear invading bacteria. Specifically, loss of functional PTPN2 promoted pathobiont invasion/uptake into macrophages and intracellular survival/proliferation by three distinct mechanisms: Increased bacterial uptake was mediated by enhanced expression of carcinoembryonic antigen cellular adhesion molecule (CEACAM)1 and CEACAM6 in <i>PTPN2</i>-deficient cells, while reduced bacterial clearance resulted from defects in autophagy coupled with compromised lysosomal acidification. In vivo, mice lacking <i>PTPN2</i> in macrophages were more susceptible to <i>m</i>AIEC infection and <i>m</i>AIEC-induced disease. Our findings reveal a tripartite regulatory mechanism by which PTPN2 preserves macrophage antibacterial function, thus crucially contributing to host defence against invading bacteria.