Multifaceted Interactions of Bacterial Toxins With the Gastrointestinal Mucosa

MR Popoff

Disclosures

Future Microbiol. 2011;6(7):763-797. 

In This Article

Future Perspective

A first medical application of enterotoxins is to develop vaccines for the prevention of diseases based on these toxins. Vaccines against toxins that disseminate through the general circulation and target organs or tissues at a distance from the GI tract are among the most efficient vaccines. Indeed, vaccines against enterotoxemia due to C. perfringens ɛ-toxin or botulism are extensively used in veterinary medicine.[223] Classically, toxin-based vaccines are derived from chemically detoxified toxins. New approaches consist in genetically detoxified toxins, such as toxin mutants or toxin subunits, which are not biologically active but retain the toxin's immunogenicity. Such an example is provided by the new generation of vaccines against botulinum toxins.[224] Protection against gastroenteritis by neutralization of enterotoxins requires a sufficient level of neutralizing antibodies locally in the intestine to be effective. Such antibodies can be acquired in neonates by ingestion of colostrum from vaccinated mothers. For example, vaccination of pregnant sows is effective to prevent young piglets from necrotic enteritis caused by C. perfringens β toxin.[225] However, enterotoxigenic and colonizing bacteria use a large set of virulence factors in addition to enterotoxins to interact with the gastrointestinal mucosa and enterotoxin only-based vaccines are not sufficient to afford an efficient protection. As such, vaccines against enterotoxigenic E. coli usually combine enterotoxin and colonization factors as antigens.[226,227] The difficulty is to induce a protective mucosal response. Most parenterally administered vaccines generate poor local protection, whereas mucosal vaccines are more efficient but require efficient antigen delivery and strong adjuvant. A great deal of effort has gone into developing vaccines against the main enterotoxins including CT, LT and ST. Interestingly, these toxins and their B-subunits are immunological modulators, notably they are efficient adjuvants for mucosal vaccines. Promising advances have been obtained using CT, LT and B-subunits as protective antigens but also in enhancing immune response to unrelated antigens, as well as in inducing a local anti-inflammatory tolerance for the treatment of autoimmune and inflammatory diseases.[228–235]

In addition, enterotoxins are very useful tools in cell biology, permitting exploration of some subtle mechanisms of physiological regulation controlling intestinal barrier integrity. This opens the door to design novel treatment and prevention. For example, research on CT and ST have led to a better understanding of regulation of fluid secretion through secondary messengers (cGMP or camp). Hormones, such as guanylin and zonulin, have been identified and characterized owing to the studies of ST and ZOT enterotoxins. Moreover, based on their specific activity, toxins can be considered not only as virulence factors, but also as therapeutic agents. For example, ZOT modulates intestinal barrier permeability. ZOT or derivative active peptides have been found to be efficient in enhancing the intestinal absorption of therapeutic agents through the paracellular pathway, and thus are promising tight junction modulators, which could be used to increase the delivery of classical drugs or antigens for vaccination through mucosa.[15,236] Another example concerns C. perfringens ɛ-toxin, which has been used to facilitate the transport of the drug bleomycin through the blood–brain barrier for the treatment of experimental malignant brain tumor in mice.[237] Another approach consists of using toxins, such as clostridial binary toxins, as delivery systems to inject foreign proteins into target cells either as therapy or in fundamental research in cell biology.[238–241] Similarly, Stx B-subunits are under development to specifically transport cytotoxic compounds in Gb3-overexpressing cancer cells, such as adenocarcinomas of the gut, or to deliver specific antigens into human dendritic cells, which selectively express Gb3, to induce a cytotoxic T lymphocyte response to viral infections or tumors.[162] Moreover, ACE and analogs have been used to treat cystic fibrosis, a genetic disease characterized by an insufficience in Cl transport. Administration of ACE was able to restore Cl secretion in the lung.[17]

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