Modulation of connexin signaling by bacterial pathogens and their toxins

Abstract

Inherent to their pivotal tasks in the maintenance of cellular homeostasis, gap junctions, connexin hemichannels, and pannexin hemichannels are frequently involved in the dysregulation of this critical balance. The present paper specifically focuses on their roles in bacterial infection and disease. In particular, the reported biological outcome of clinically important bacteria including Escherichia coli, Shigella flexneri, Yersinia enterocolitica, Helicobacter pylori, Bordetella pertussis, Aggregatibacter actinomycetemcomitans, Pseudomonas aeruginosa, Citrobacter rodentium, Clostridium species, Streptococcus pneumoniae, and Staphylococcus aureus and their toxic products on connexin- and pannexin-related signaling in host cells is reviewed. Particular attention is paid to the underlying molecular mechanisms of these effects as well as to the actual biological relevance of these findings.

Pseudomonas aeruginosa–Induced Apoptosis in Airway Epithelial Cells Is Mediated by Gap Junctional Communication in a JNK-Dependent Manner

“…Gap junctions and hemichannels are targets of bacterial pathogens and their toxins (reviewed by Ceelen et al) (7). S. flexneri, an invasive bacterium that replicates within intestinal epithelial cells, received particular attention.…”

“…The junctional complex consists of anchoring junctions (desmosomes and adherens junctions), occluding junctions (tight junctions), and communicating junctions (gap junctions). Gap junctions have been recently involved in bacterial infections and several infectious diseases, including CF (7). Gap junctions are made by docking of two hexameric hemichannels (connexons) of two apposed cells, thus composed of 12 proteins called connexins.…”

“…Gap junctions ensure the direct cell-to-cell transfer of ions, sugars, nucleotides, short peptides, and second messengers (8). Bacterial contact, bacterial internalization, and/or bacterial cytotoxins have been found to modulate hemichannel activity and gap junctional communication in the host epithelium, resulting in imbalanced homeostasis (7,9,10). It was recently reported that gap junction channels favor the cell-to-cell spread of an inflammatory response dominated by IL-8 production upon Shigella flexneri internalization in an intestinal epithelial cell line (11).…”

Connexin hemichannels influence genetically determined inflammatory and hyperproliferative skin diseases

“…Perhaps most persuasive for the broader scientific community is a rapidly accumulating body of evidence to suggest that connexin-associated cellular events in the skin minimally encompass keratinocyte proliferation [104,105], differentiation [106,107], adhesion [108,109], migration [110–112], inflammation [113–116], and innate immune surveillance [47,117,118]. KID syndrome is a particularly suitable model for discussion, being that these patients live at the intersection of inflammatory, infectious, and neoplastic processes.…”

“…Also noteworthy is a putative pro-inflammatory interplay between paracrine signaling via connexin hemichannels, the cutaneous microflora, and opportunistic pathogens [117]. Bacterial cell wall components are observed to differentially influence expression levels and open probability of Cx26 and Cx43 hemichannels [47,118].…”