Safeguarding intestine cells against enteropathogenic Escherichia coli by intracellular protein reaction, a preventive antibacterial mechanism.

Abstract

A critical problem in the fight against bacterial infection is the rising rates of resistance and the lack of new antibiotics. The discovery of new targets or new antibacterial mechanisms is a potential solution but is becoming more difficult. Here we report an antibacterial mechanism that safeguards intestine cells from enteropathogenic Escherichia coli (EPEC) by shutting down an infection-responsive signal of the host intestine cell. A key step in EPEC infection of intestinal cells involves Tir-induced actin reorganization. Nck mediates this event by binding with Tir through its SH2 domain (Nck-SH2) and with WIP through its second SH3 domain (Nck-SH3.2). Here we report the design of a synthetic peptide that reacts precisely with a unique cysteine of the Nck-SH3.2 domain, blocks the binding site of the Nck protein, and prevents EPEC infection of Caco-2 cells. Oral update of this nontoxic peptide before EPEC administration safeguards mice from EPEC infection and diarrhea. This study demonstrates domain-specific blockage of an SH3 domain of a multidomain adaptor protein inside cells and the inhibition of Tir-induced rearrangement of the host actin cytoskeleton as a previously unknown antibacterial mechanism.

• Authors: Jiaming Qiu, Yunyu Nie, Yuan Zhao, Yu Zhang, Linting Li, Rui Wang, Miaomiao Wang, Sheng Chen, Jianhao Wang, Yong-Qiang Li, Jiang Xia
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 117 Issue 10 Pg. 5260-5268 (03 10 2020) ISSN: 1091-6490 [Electronic] United States
• PMID: 32094196 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Actins
• Adaptor Proteins, Signal Transducing
• Antimicrobial Cationic Peptides
• Escherichia coli Proteins
• Nck protein
• Oncogene Proteins
• Receptors, Cell Surface
• Tir protein, E coli

Topics

• Actins (metabolism)
• Adaptor Proteins, Signal Transducing (antagonists & inhibitors, chemistry, metabolism)
• Animals
• Antimicrobial Cationic Peptides (pharmacology, therapeutic use)
• Caco-2 Cells
• Enteropathogenic Escherichia coli (drug effects, metabolism)
• Escherichia coli Infections (prevention & control)
• Escherichia coli Proteins (antagonists & inhibitors, chemistry, metabolism)
• Host-Pathogen Interactions (drug effects)
• Humans
• Intestinal Mucosa (metabolism, microbiology)
• Mice
• Mice, Inbred C57BL
• Oncogene Proteins (antagonists & inhibitors, chemistry, metabolism)
• Protein Binding
• Receptors, Cell Surface (antagonists & inhibitors, chemistry, metabolism)
• Signal Transduction
• src Homology Domains