Toxins are powerful pathogenicity factors produced by certain bacteria, fungi, animals,
and plants which mediate drastic interactions of these pathogens on the organism host.
Notably, bacterial toxins were the first compounds which were identified as responsible
for severe bacterial diseases in man and animals. Numerous studies and publications
were dedicated to bacterial toxin characterization and deciphering of their mechanisms
of action. The “Bacterial Toxins” section of the journal Toxins is entirely devoted
to this topic. Classically, bacterial toxins are divided into exotoxins and endotoxins.
While endotoxins are membrane compounds of Gram-negative bacteria which elicit an
inflammatory response in host, exotoxins are secreted proteins which act locally and
at distance of the bacterial colonization site. Specific factors produced by invasive
bacteria, and called virulence factors, are related to exotoxins and some of them
share similar enzymatic activities to those of exotoxins. However, in contrast to
exotoxins, the virulence factors are directly injected into the cell where the bacterium
is attached by specific secretion types, such as the type III secretion system, and
their activity is restricted to the attacked cell. Numerous works, publications, and
meetings have been related to these fascinating toxin proteins which display multiple
activities and functions; such an example is the Sourcebook of Bacterial Protein Toxins
[1] or the diverse special issues of the journal Toxins. Indeed, bacterial toxins
show an extreme diversity regarding their size (from 15 to more than 2700 amino acids),
mode of secretion (different bacterial secretion types), structure (mono, binary,
ternary, or multiple complex proteins), membrane/intracellular receptor recognition,
enzymatic activity, or specific mode of action such as pore-forming activity.
In the last decades, a great effort has been done to unravel the mechanisms of action
of these very active proteins able to induce so severe symptoms in higher organisms.
Clostridium perfringens alpha toxin was the first bacterial toxin identified as developing
an enzymatic activity consisting of phospholipase C activity at the cell membrane
surface [2]. Then, diphtheria toxin (DT) was the first toxin that was characterized
to exert a novel enzymatic activity intracellularly [3,4]. Thereby, DT modifies the
elongation factor-2 (EF-2) by ADP-ribosylation, leading to inhibition of cell protein
synthesis and cell death. ADP-ribosylation was then recognized to be shared by numerous
other intracellularly-active toxins. Other bacterial toxins develop an enzymatic activity
commonly used by many cellular or bacterial enzymes, such as protease, glucosylase,
DNase, or RNase, but towards a specific intracellular target promoting specific effects.
This is the case of clostridial neurotoxins which specifically cleaves SNARE proteins
in target neuronal cells, thus inhibiting the evoked release of neurotransmitters.
Since bacterial toxins interact with specific cellular compounds and alter specific
cellular processes, they are highly relevant tools not only to better understand pathogenicity
mechanisms, but also to unravel physiological processes. An emblematic example is
that of Clostridium botulinum C3 exoenzyme, which was characterized as an ADP-ribosyltransferase
of a novel G-protein of unknown function, termed Rho, from the Ras superfamily. C3
exoenzyme was found to break the actin filaments in cultured epithelial cells and
this opened the door to understanding the regulation of actin filament polymerization
via the small GTPases of the Rho family [5]. Therefore, bacterial toxins are at the
frontier of various disciplines including bacteriology, cellular biology, molecular
biology, structural biology, biochemistry, genetics, immunology, and vaccinology.
The diverse properties of bacterial toxins are well documented, notably in the multidisciplinary
special issues of the journal Toxins.
More recently, novel advances have been performed in bacterial toxins which have been
mainly facilitated by the development/improvement of molecular technologies. Indeed,
whole genome sequencing of saprophytic and pathogenic bacteria with subsequent genomics
analysis allowed the identification of novel toxins and the exploration of their spreading
and evolution in the bacterial world. For example, typhoid toxin was initially suspected
in cells invaded by Salmonella typhi and was subsequently characterized by genomic
analysis and crystal structure, which revealed a novel toxin organization consisting
of two distinct enzymatic subunits and five binding subunits. Typhoid toxin seems
to have evolved from assembly of several ancestor toxin genes spread in other bacteria,
such as cytolethal distending toxins and pertussis toxin [6]. The rapidly increasing
progress in the whole genome sequencing of microorganisms would probably result in
identification of novel toxins and in-depth understanding of their evolution. Moreover,
refinement of the crystal structure investigations allowed unravelling the 3D structure
of large or complex toxins, such as the whole structure of the large clostridial glucosylating
toxin A from Clostridium difficile [7] or botulinum progenitor toxin complex [8].
However, many aspects of these multifunctional toxin proteins remain to be discovered.
Albeit cellular receptors have been identified for some toxins, they are largely unknown
for many others. Strategic features, such as toxin dissemination into the host to
target cells, interaction with the cell membrane, crossing the phospholipid bilayer,
intracellular trafficking, and precise mechanisms of cell alteration are still under
investigation for many toxins.
In addition to their interest in fundamental science, bacterial toxins are key players
in various applied developments, including tools for diagnosis, prevention, and therapy
of diseases, due to toxigenic bacteria. Indeed, the diagnosis of several diseases
is based on the detection and identification of toxins in biological and/or environmental
samples, such as foods. The development of sensitive and rapid in vitro methods of
toxin characterization are still in progress using new or improved technologies, such
as mass spectrometry, refined ELISA, or fluorescent techniques. Since the pioneering
historical works, detoxified toxins (anatoxins) were shown to elicit a solid preventive
response against diseases due to toxigenic bacteria. Anatoxins are among the most
efficient vaccines against bacterial diseases. Recombinant toxin subunits, which are
biologically inactive, but retain the immunogenicity, offer the advantage to be safer
than the classical detoxified toxins. Development of efficient toxin inhibitors are
of major importance (see the special issue of Toxins edited by H. Barth). Although
bacterial toxins are very poisonous compounds, some of their properties have powerful
therapeutic applications. The most representative example is that of botulinum toxins
which are used for their anti-cholinergic effects. Thereby, the most potent toxins
are the drugs which have the most numerous medical indications from the treatment
of dystonia, strabismus, hypersecretory activity of cholinergic glands, urinary bladder
dysfunction, pain, cosmetology, etc. Botulinum toxins are mainly used as wild-type
purified proteins, but engineering of these molecules is in progress to exploit specific
properties of these toxins, such as therapeutic effects on sensitive neurons and the
treatment of pain [9]. Recombinant toxins have also been engineered to specifically
kill malignant cells (immunotoxins), or to transport therapeutic compounds into specific
host compartments hardly accessible by routine administration pathways, such as the
central nervous system. In addition, toxin development concerns not only medical applications,
but also broad technical innovations. Thereby, the specific pore-forming activity
of Staphylococcus aureus alpha toxin is used in novel processes of DNA sequencing
[10].
Bacterial toxins are an increasing field of interest for scientists, health professionals,
teachers, and students from various disciplines. The journal Toxins, which gathers
toxin articles in specific sections and special issues, is quite appropriate to receive
high-quality manuscripts, reviews, editorials, comments, and to promote fruitful discussions
in the scientific community. We hope that Toxins will be more and more attractive
to receive original and pertinent submissions.