Pathogenic Bacterial Proteins and their Anti-Inflammatory Effects in the Eukaryotic Host

Abstract

Bacteria use multiple strategies to bypass the inflammatory responses in order to survive in the host cells. In this review, we discuss the mechanism of the bacerial proteins in inhibiting inflammation. We highlight the anti-inflammatory roles of the type three secretion proteins including Salmonella AvrA, Enteropathogenic Escherichia coli Cif, and Yersinia YopJ, Staphylococcus aureus extracellular adherence protein, and Chlamydia proteins. We also discuss the research progress on the structures of these anti-inflammatory bacterial proteins. The current therapeutic methods for diseases, such as inflammatory bowel diseases, sclerosis, lack influence on the course of chronic inflammation and infection. Therefore, based on the molecular mechanism of the anti-inflammatory bacterial proteins and their 3-Dimension structure, we can design new peptides or non-peptidic molecules that serve as anti-inflammatory drugs without the possible side effect of promoting bacterial infection.

Fig. (1). Schematic model for the anti-inflammatory function of Salmonella effector AvrA in the intestinal epithelial cells

There is a cross-talk between β-catenin and NF-κB pathways in Salmonella-epithelial interaction. AvrA inhibits the NF-κB pathways. AvrA protein acts as a deubiquintinase to stabilize β-catenin and IκBα, thus inhibiting NF-κB pathways and activating the β-catenin pathway. AvrA stabilizes intestinal epithelial cell tight Junctions (TJ). AvrA also possesses acetyltransferase activity toward MAPKK and inhibits c-Jun N-terminal kinase and NF-κB signaling pathways. The role of AvrA represents a highly refined bacterial strategy that helps the bacteria survive in the host, dampens the inflammatory response, and prevents the apoptotic elimination in cells that have perceived microbial compromise. AvrA may play a role in stabilizing TJs and balancing the opposing action of other bacterial effectors.

Fig. (2). Inactivation of NF-κB and MAPK pathways (simplified version) by the bacterial proteins

As shown here, MAPK signaling through sequential steps involves TRAF6, TAK1, and MAPKK. A parallel NF-κB pathway involves TRAF6, TAK1, IKKβ, IκBα phosphorylation (P), ubiquitination (Ub), NF-κB translocation, activation of NF-κB transcription, and target gene expression. Bacterial TTSS effectors including Salmonella AvrA, SseL, Yersinia YopJ, and Chlamydia ChlaDub1/2 act as deubiquitinases to target the ubiquitination of IκBα, thus inhibiting the NF-κB activity. Chlamydia protein CT441 cleaves the NF-κB subunit p65 and attenuate the NF-κB activity. Additionally, Shigela OspF modifies phosphorylation of histone H3 at Ser10 increases chromatin accessibility to transcription factor NF-κB. Acting as a broad-specificity deubiquitinase, YopJ removes Ub from proteins, including TRAF6 and IκBα. MAPKK and IKKβ are activated by phosphorylation of serine or threonine residues in their activation loops. YopJ inactivates these pathways. The MAPK pathway is modulated by AvrA through acetylation. AvrA, YopJ, and OspF inhibit the c-JNK pathway, attenuate the inflammatory responses, and interfere with the cell apoptotic process.