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Bacterial Toxins

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Introduction

Pathogenic bacteria possess an array of virulence factors that allow them to colonize, invade and replicate within an immune competent host. Many bacteria produce toxins, enzymes and pigments, toxins and enzymes play important role in pathogenicity. Bacterial toxins are virulence factors that manipulate host cell functions and take over the control of vital processes of living organisms to favor microbial infection. The mechanisms by which pathogens interfere with the host cellular processes often involve toxins secreted across their outer membrane (envelope) through different secretion systems (type I, II or V, outer membrane vesicles etc.) or directly injected into the host cell through the bacterial type III secretion system (T3SS) or T4SS secretion apparatus.

Cellular processes targeted by bacterial toxins Fig. 1 Cellular processes targeted by bacterial toxins (Giampietro Schiavo & F. Gisou van der Goot. 2001)

Classification

Bacterial toxins show an extreme diversity regarding their source, size, structure, mode of secretion, membrane/intracellular receptor recognition, specific mode of action.

Bacterial toxins are mainly divided into two types based on their source: exotoxins and endotoxins.

Exotoxins are usually heat labile proteins secreted by certain species of bacteria which diffuse into the surrounding medium. An exotoxin can cause damage to the host by destroying cells or disrupting normal cellular metabolism. They are highly potent and can cause major damage to the host. The pathogenic bacteria that produce exotoxins mainly include Clostridium tetani, Clostridium botulinum, Clostridium perfringens, Corynebacterium diphtheriae, Group A streptococcus, Staphylococcus aureus, Shigella dysenteriae, Yersinia pestis, Vibrio cholerae, Pseudomonas aeruginosa, etc.

Endotoxin is a type of lipopolysaccharide (LPS), consisting of lipid A (usually 6 acyl chains attached to a phosphorylated disaccharide), attached to the ‘core’ (a short sugar chain with various modifications), which is attached to the O-antigen (a long linear chain of sugars of variable length). Endotoxin is a major component of the outer membrane of gram-negative bacteria, with lipid A in the membrane and the O-antigen constituting the outer-facing surface of the bacterium. Soluble endotoxin is released when bacteria are destroyed, but is also released physiologically as outer membrane vesicles. There are a few endotoxins that are not related to LPS, such as the delta endotoxin proteins produced by Bacillus thuringiensis.

Structure of lipopolysaccharide (LPS) Fig. 2 Structure of lipopolysaccharide (LPS) (Bidne KL, et al. 2018)

Bacterial toxins are mainly divided into three types based on their mode of action: type I toxins, type II toxins and type III toxins.

Type I toxins disrupt host cells without the need to enter the cells. Few intracellular targets of type I toxins have been identified, possibly due to the difficult nature of analysing proteins that are poisonous to their bacterial hosts. These include superantigens (SAgs) produced by S. aureus and S. pyogenes.

Type II toxins, such as hemolysins and phospholipases destroy host cell membranes to invade and interrupt host defense processes within the cell. Damages host cells release danger-associated molecular patterns (DAMPs) that bind to pattern-recognition receptors (PRRs) causing the release of inflammatory cytokines

Type III toxins, also known as A/B toxins due to their binary structure; disrupt host cell defenses to allow dissemination to remote organs. The B component of these toxins binds to the host cell surface, while the A component possess the enzymatic activity to damage the cell.

Application

With increasing utilization of genomics and proteomics techniques, there is a greater understanding of microbial pathogenesis and their role in clinical disease. In addition to fundamental science, bacterial toxins are key players in various applied developments, including tools for diagnosis, prevention, and therapy of diseases, due to toxigenic bacteria.

Mechanism of action of botulinum toxin type A Fig. 3 Mechanism of action of botulinum toxin type A (Arnon SS, et al. 2001 and Kukreja & Singh 2015)

  • Diagnosis

There is a spectrum of importance in detecting bacterial toxins for diagnostic purposes. The diagnosis of several diseases is based on the detection and identification of toxins in biological and/or environmental samples. Like pertussis toxin routinely detected for tracheobronchitis diagnose. Routine toxin detection occurs in both frontline clinical microbiology and reference laboratories and depends on the pathogen involved, the assay performed, and also the patient population (and corresponding prevalence of disease).

  • Prevention

Chemically detoxified bacterial toxins (toxoids) have been successfully used as vaccines for the prevention of many bacterial infectious diseases. Non-toxic derivatives of bacterial toxins can be obtained by mutagenesis of the toxin genes. These genetically inactivated toxins are superior to the classical toxoids both in safety and in immunogenicity and therefore they should replace the old toxoids in the existing vaccines. In addition, they represent a novel class of immunogens with unique properties, some of which may be used for innovative approaches to vaccination.

  • Therapy

Although bacterial toxins are very poisonous compounds, some of their properties have powerful therapeutic applications. The most representative example is that of botulinum toxins, the 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. The two bacterial toxins in targeted biological therapies are diphtheria toxin and pseudomonas exotoxin A, each containing a binding and a catalytic domain separated by a translocation domain, and are able to kill tumor cells by inhibition of protein synthesis. Both toxins have been extensively studied in hematological malignancies.

Detection methods

  • Biological assays

Bioassays and related tests remain the method of choice for some bacterial toxins (e. g. botulinum toxins). Many bioassay formats have been described, including whole animal tests (e. g. the mouse lethality test, monkey and kitten emesis tests, and rabbit and guinea-pig skin tests), part-animal tests (e. g. ileal loop tests) and cell culture systems (e. g. Chinese hamster ovary (CHO) cells).

  • Immunological assays

Immunological assays are much simpler and cheaper than biological assays and have therefore been widely adopted. The techniques for the detection of bacterial toxins including gel diffusion assays, hemagglutination, coagglutination, reverse passive latex agglutination, enzyme-linked immunosorbent assay, enzyme-linked immunofiltration assay and radioimmunoassay.

  • Nucleic acid probes and polymerase chain reaction

DNA-hybridization and the polymerase chain reaction (PCR) are techniques commonly used to detect bacterial toxins. DNA-techniques have most often been used in a “culture confirmation” fashion, i.e., bacteria are enriched and sometimes even purified by traditional culture procedures and thereafter identified by the use of DNA-based methods.

Creative Diagnostics offers a range of high-quality bacterial toxin products for use in a wide range of research applications. If you are interested in finding out more about our bacterial toxin products, please feel free to contact us.

References:

  1. Ana do V, Didier C, Sandra S. Bacterial Toxins as Pathogen Weapons Against Phagocytes. Frontiers in microbiology. (2016). 7: 42
  2. Michel RP. “Bacterial Toxins” Section in the Journal Toxins: A Fantastic Multidisciplinary Interplay between Bacterial Pathogenicity Mechanisms, Physiological Processes, Genomic Evolution, and Subsequent Development of Identification Methods, Efficient Treatment, and Prevention of Toxigenic Bacteria. Toxins. (2018). 10(1):44
  3. Jessica DF. Clinically Important Toxins in Bacterial Infection: Utility of Laboratory Detection. Clinical Microbiology Newsletter. (2020). 42(20):163-170.
  4. D. W. Pimbley, P. D. Patel. A review of analytical methods for detection of bacterial toxins. Journal of Applied Microbiology Symposium Supplement. (1998). 84 (S1):98S-109S.

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