Editorial: Bacterial Exotoxins: How Bacteria Fight the Immune System

摘要

The Editorial on the Research Topic Bacterial Exotoxins: How Bacteria Fight the Immune System Upon infection with a bacterial pathogen, the body initiates both innate and adaptive immune responses with the ultimate goal to eliminate the invader and to return to homeostasis. Occasionally, however, the body may react inadequately, resulting in collateral damage to tissues if the response it too strong or in a failure to eradicate the pathogen if the response is too weak or ephemeral. Functionally diverse toxins released by bacteria during infection can contribute considerably to the outcomes of the immune response. For example, bacterial toxins may mediate bacterial evasion of immune recognition, facilitate dwelling within protected niches of eukaryotic cells, or modulate pro-inflammatory responses. Furthermore, in recent years, it has become evident that beyond their canonical actions, bacterial toxins may initiate other cellular responses. For example, besides inducing cytolysis, pore-forming toxins may also induce autophagy, pyroptosis, or activation of the MAPK pathways, resulting in adjustment of the host immune response to infection and modification of inflammatory responses both locally and systemically ( 1 , 2 ). Exotoxins can be single polypeptides or heteromeric protein complexes that act on different parts of the cells. At the cell surface, they may insert into the membrane to cause damage, bind to receptors to initiate their uptake, or facilitate interactions with other cell types. For intracellular activity, exotoxins need to be translocated across the eukaryotic membrane. Gram-negative bacteria can directly inject effector proteins in a receptor-independent manner by use of specialized needle apparatus such as bacterial type II, type III, or type IV secretion systems. Other methods of translocation include the phagocytic uptake of bacteria followed by toxin secretion and receptor-mediated endocytosis. Receptor-based uptake allows the targeting of distinct cell types uniquely expressing the receptor. It is initiated by the binding of heteromeric toxin complexes to cell surfaces and is completed by the translocation of the effector proteins across the endosomal membrane. Once in the cytosol, toxins interact with specific eukaryotic target proteins to cause post-translational modifications of host proteins that often result in the manipulation of cellular signaling cascades and inflammatory responses ( 3 ). The intention of this special issue on bacterial exotoxins is to gather current knowledge on the interaction of these versatile effector proteins with the host immune system and to describe mechanisms of immune modification and evasion. We thank the authors of the following 16 articles for providing diverse overviews, comprehensive reviews, and intriguing new data regarding the effects on, and interactions with, three important groups of immune function: (1) barrier cells such as fibroblasts, and epithelial and endothelial cells that are responsible for mediating local immune responses, (2) innate phagocytic cells, and (3) cells of the adaptive arm of immunity. The first group of manuscripts addresses the interaction of bacterial toxins of both Gram-positive and Gram-negative bacteria with initial barrier cells. Mayer et al. explore the effects of Shiga Toxin (Stx) expressed by enterohemorrhagic E. coli on renal endothelial and epithelial cells. In the kidneys, Stx causes hemolytic uremic syndrome, which can result in renal failure. The authors found that Stx-induced damage of renal cells stimulates the release of host-derived damage-associated molecular patterns (DAMPs), such as histones or high-mobility group protein B1 (HMGB1), and that these contribute to the severity of the disease. Ashida et al. review how Shigella , a pathogen of the intestinal tract that causes dysentery, uses effector proteins that are injected into host target cells via a type-III secretion system to induce cell death, to modulate protein trafficking and signaling, and to ultimately interfere with both innate and adaptive immunity. Moreover, the poultry pathogen Salmonella pullorum expresses an iron-storage protein called bacterioferritin that appears to be a major antigen for the chicken humoral response to S. pullorum infection ( Xu et al. ). Using a chicken fibroblast cell line, the authors furthermore identify the induction of the type I interferon IFN-β as a major consequence of bacterioferritin exposure. The last article on the effects of toxin on host barrier function is by von Hoven et al. who studied the pore-forming α-toxin of Staphylococcus aureus . Using mouse embryonic fibroblasts, the authors show that stress-induced basal phosphorylation of the eukaryotic translation initiation factor 2α (eIF2α) results in tolerance to the toxin. Macrophages, however, are tolerant to α-toxin independent of such a stress response, underlining the fact that various host cell types can mediate different layers of tolerance