Activation of the TRIF pathway and downstream targets results in the development of precancerous lesions during infection with Helicobacter.

Bali, P.; Lozano-Pope, I.; Hernandez, J.; Estrada, M. V.; Corr, M.; Turner, M. A.; Bouvet, M.; Benner, C.; Obonyo, M.

doi:10.1101/2023.06.04.543598

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bioRxiv · 10.1101/2023.06.04.543598

Activation of the TRIF pathway and downstream targets results in the development of precancerous lesions during infection with Helicobacter.

Bali, P.·Lozano-Pope, I.·Hernandez, J.·Estrada, M. V.·Corr, M.·Turner, M. A.·Bouvet, M.·Benner, C.·Obonyo, M.

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Abstract

Helicobacter pylori (H. pylori) infection is an established cause of many digestive diseases, including gastritis, peptic ulcers, and gastric cancer. However, the mechanism by which infection with H. pylori causes these disorders is still not clearly understood. This is due to insufficient knowledge of pathways that promote H. pylori-induced disease progression. We have established a Helicobacter-induced accelerated disease progression mouse model, which involves infecting mice deficient in the myeloid differentiation primary response 88 gene (Myd88-/-) with H. felis. Using this model, we report here that that progression of H. felis-induced inflammation to high-grade dysplasia was associated with activation of type I interferon (IFN-I) signaling pathway and upregulation of related downstream target genes, IFN-stimulated genes (ISGs). These observations were further corroborated by the enrichment of ISRE motifs in the promoters of upregulated genes. Further we showed that H. felis-induced inflammation in mice deficient in Toll/interleukin-1 receptor (TIR)-domain-containing adaptor inducing interferon-{beta} (TRIF, TrifLps2) did not progress to severe gastric pathology, indicating a role of the TRIF signaling pathway in disease pathogenesis and progression. Indeed, survival analysis in gastric biopsy samples from gastric cancer patients illustrated that high expression of Trif was significantly associated with poor survival in gastric cancer.

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Bali, P., Lozano-Pope, I., Hernandez, J., Estrada, M. V., Corr, M., Turner, M. A., Bouvet, M., Benner, C., Obonyo, M.. 2023-06-06. Activation of the TRIF pathway and downstream targets results in the development of precancerous lesions during infection with Helicobacter.. https://doi.org/10.1101/2023.06.04.543598

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