Bacterial Genotoxin Accelerates Transient Infection-Driven Murine Colon Tumorigenesis.

Abstract

Chronic and low-grade inflammation associated with persistent bacterial infections has been linked to colon tumor development; however, the impact of transient and self-limited infections in bacterially driven colon tumorigenesis has remained enigmatic. Here we report that UshA is a novel genotoxin in attaching/effacing (A/E) pathogens, which include the human pathogens enteropathogenic Escherichia coli, enterohemorrhagic E. coli, and their murine equivalent Citrobacter rodentium (CR). UshA harbors direct DNA digestion activity with a catalytic histidine-aspartic acid dyad. Injected via the type III secretion system (T3SS) into host cells, UshA triggers DNA damage and initiates tumorigenic transformation during infections in vitro and in vivo. Moreover, UshA plays an indispensable role in CR infection-accelerated colon tumorigenesis in genetically susceptible Apc MinΔ716/+ mice. Collectively, our results reveal that UshA, functioning as a bacterial T3SS-dependent genotoxin, plays a critical role in prompting transient and noninvasive bacterial infection-accelerated colon tumorigenesis in mice. SIGNIFICANCE: We identified UshA, a novel T3SS-dependent genotoxin in A/E pathogens that possesses direct DNA digestion activity and confers bacterially accelerated colon tumorigenesis in mice. Our results demonstrate that acute and noninvasive infection with A/E pathogens harbors a far-reaching impact on the development of colon cancer.This article is highlighted in the In This Issue feature, p. 1.

• Authors: Yue Liu, Kai Fu, Eric M Wier, Yifan Lei, Andrea Hodgson, Dongqing Xu, Xue Xia, Dandan Zheng, Hua Ding, Cynthia L Sears, Jian Yang, Fengyi Wan
• Journal: Cancer discovery (Cancer Discov) Vol. 12 Issue 1 Pg. 236-249 (01 2022) ISSN: 2159-8290 [Electronic] United States
• PMID: 34479870 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: ©2021 American Association for Cancer Research.

Chemical References

• Mutagens

Topics

• Animals
• Cell Line, Tumor (drug effects)
• Cell Transformation, Neoplastic (pathology)
• Citrobacter rodentium (pathogenicity)
• Colorectal Neoplasms (microbiology, pathology)
• Disease Models, Animal
• Enteropathogenic Escherichia coli (pathogenicity)
• Humans
• Mice
• Mice, Inbred C57BL
• Mutagens (pharmacology)