Exacerbated salmonellosis in poly(ADP-ribose) polymerase 14 deficient mice

Abstract

Salmonella enterica subspecies enterica serovar Typhimurium (S. Typhimurium) is an enteropathogen annually causing millions of acute infections ranging from gastroenteritis to life-threatening invasive systemic disease. Strong mucosal inflammation is characteristic for the infection driven by the innate immune receptor activation but also directly by the invading bacterium. It remains unknown how and at which point the mucosal inflammation turns anti-bacterial and how the tissue homeostasis is restored. Here, we investigated the expression and function of poly(ADP-ribose)polymerase (Parp14), a known cytoplasmic and nuclear regulatory protein of immune cells, in the mouse streptomycin-pretreatment model of S. Typhimurium infection. In the infected mice, Parp14 expressing cells, some of which were macrophages, were detected throughout the gastrointestinal tract. However, the most strongly Parp14 expressing cells were the epithelial cells. Based on small intestine single cell RNA-Seq analysis of different epithelial cell types, the expression of parp14 was pronounced in the enterocytes and Tuft cells. Mice with a body-wide genetic deficiency of Parp14 suffered from exacerbated S. Typhimurium colitis. The histopathological analysis of the large intestine revealed increased immune cell infiltration, Goblet cell loss, and epithelial erosion. At the same time lower numbers of viable bacteria were detected. Based on a bulk tissue RNA-Seq analysis, transcriptional signatures either missing or down-regulated in the infected Parp14 deficient mice were detected. These signatures were enriched with genes related to cell adhesion, cell division and cytoskeletal rearrangements, and genes related to infection and immune responses. It appears that Parp14 has potential functions in the regulation of tissue architecture and mucosal inflammation in the large intestine of S. Typhimurium infected mice.