Editorial: Why still study bacterial toxins in the third millennium?

Pathogenic bacteria possess an array of virulence factors that allow them to colonize, invade and replicate within an immune competent host, and bacterial toxins are among the most sophisticated virulence factors. These effectors can target and disrupt cellular membranes (Peraro and van der Goot 2015), or act intracellularly and be highly specific for their target (Lemichez and Barbieri 2013). Some toxins have a level of complexity that allows them to exert multiple functions, e.g., pore forming toxins and regulators of intracellular processes (Satchell 2011; Cassidy and O'Riordan 2013). Identification of the toxins’ mode of action and characterization of their receptors and internalization routes have allowed the production of prophylactic vaccines and the understanding of their roles in the pathogenesis of bacteria-induced disease (Alouf, Ladant and Popoff 2015). Bacterial toxins have also been instrumental tools in biomedical research to identify basic cellular processes (Schiavo and van der Goot 2001) and have been employed as drugs for treatment of serious diseases or in the cosmetic industry (Antignani and Fitzgerald 2013; Luvisetto et al.2015).

In spite of many years of research on bacterial toxins, this field still offers surprising discoveries, such as identification of new toxins, or novel biological facets of already identified effectors, thus contributing to elucidate better the complexity of the host-microbe interaction.

Advances in the field of bacterial toxins are regularly presented and discussed at the dedicated European Workshop on Bacterial Protein Toxins (ETOX), which is held every second year, making a roundtrip of great locations throughout European countries. The recent successful ETOX17 meeting was held in Braga, Portugal, in June 2015. The scientific excitement and curiosity, which is the key element of each ETOX meeting, was permeated by the sadness of the loss of two of the most prominent researchers in the field and founding fathers of this event: Profs Josef Alouf and Sjur Olsnes.

To honor their memory and maintain alive their spirit, this thematic issue of FEMS Pathogens and Disease reports some of the very exciting advances presented at the ETOX17 in form of mini-reviews and original papers.

The topics presented deal with several interesting emerging issues, and some of them are briefly highlighted in the next paragraphs. Rosadi et al. discuss the potential role of a family of bacterial toxins in carcinogenesis, either due to their genotoxic effect on DNA or their ability to alter key eukaryotic processes, such as cellular signaling and cell death. The already complex world of bacterial toxins just got bigger due to the newly discovered novel two-gene ADP-ribosyltransferase toxin families related to pertussis toxin in Escherichia coli (Jobling). Bugalhaão et al. review the effects of bacterial toxins that function as direct actin nucleators, a different but highly efficient mechanism to alter the actin cytoskeleton, compared to the mode of action of previously identified bacterial toxins, which either mimics Nucleation Promoting Factors or activates upstream small GTPases. A recurrent theme in this research field is the structural analysis of the sophistication to which bacterial toxins have evolved over hundreds of millions of years to adapt to the pathogen-host co-evolution. A beautiful example of structural insight into adaptation of the ADP-ribosylating C3 toxin activity on the host RhoA GTP-ase is discussed in this issue (Tsuge et al.). The authors have identified an ADP-ribosylating turn-turn (ARTT) loop in C3 toxin of Clostridiae that is involved in substrate specificity and recognition, and describe how this adapts to the structure of RhoA upon protein-protein interaction and induces conformational changes within the host target protein.

This thematic issue further analyses the complexity of the mode of action of bacterial toxins, which can have multiple functions, such as the Bordetella pertussis CyaA, which acts as a cytolysin that forms cation-selective pores in target membranes, but can also be translocated across the host cell membrane of phagocytes and exert the function of adenylyl cyclase, leading to increased levels of intracellular cAMP (Masin et al. and Wald et al.).

Development of sensitive and rapid detection system for toxins and their biological activity is essential for a proper diagnosis and treatment of infectious disease that can be life-threatening. Kolesnikov and colleagues have developed an ultra sensitive PCR-based assay for detecting proteolytic activity of anthrax and botulinum toxins.

In addition, several minireviews in this special issue will become a comprehensive source of references for the research community on the Rho-modifying toxins (Aktories), intact cell imaging for toxins and effectors (Zuverink and Barbieri), the very large Multiple Activities RTX toxins as effector delivery platforms (Gavin and Satchell), or the intriguing VapBC toxin-anti-toxin (VapBC TA) systems, where tRNA cleavage by the VapC toxin regulates bacterial growth in response to stress (Cruz and Woychik).

The mini-reviews and the original papers presented in this thematic issue show that the field of bacterial toxins is more alive than ever and many years of exciting research await in front of us.

All interested readers are cordially invited to the next ETOX18 meeting, in Paris, France on June 24-28, 2017.

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