Lipid nanodiscs influence α-Syn oligomerization rates M. Jakubec et al.

No abstract

Infection with enterotoxigenic Escherichia coli (ETEC) is an important cause of diarrhea-related illness and death among children under 5 years of age in low- and middle-income countries (LMIC). Recent studies have found that it is the ETEC subtypes that produce the heat-stable enterotoxin (ST), irrespective of whether they also secrete the heat-labile enterotoxin (LT), which contribute most importantly to the disease burden in children from LMIC. Therefore, adding an ST toxoid would importantly complement ongoing ETEC vaccine development efforts. The ST's potent toxicity, its structural similarity to the endogenous peptides guanylin and uroguanylin, and its poor immunogenicity have all complicated the advancement of ST-based vaccine development. Recent remarkable progress, however, including the unprecedented screening for optimal ST mutants, mapping of cross-reacting ST epitopes and improved ST-carrier coupling strategies (bioconjugation and genetic fusion), enables the rational design of safe, immunogenic, and well-defined ST-based vaccine candidates.

Infection with enterotoxigenic Escherichia coli (ETEC) is a common cause of childhood diarrhea in low-and middle-income countries, as well as of diarrhea among travelers to these countries. In children, ETEC strains secreting the heatstable toxin (ST) are the most pathogenic, and there are ongoing efforts to develop vaccines that target ST. One important challenge for ST vaccine development is to construct immunogens that do not elicit antibodies that cross-react with guanylin and uroguanylin, which are endogenous peptides involved in regulating the activity of the guanylate cyclase-C (GC-C) receptor. We immunized mice with both human ST (STh) and porcine ST (STp) chemically coupled to bovine serum albumin, and the resulting sera neutralized the toxic activities of both STh and STp. This suggests that a vaccine based on either ST variant can confer cross-protection. However, several anti-STh and anti-STp sera cross-reacted with the endogenous peptides, suggesting that the ST sequence must be altered to reduce the risk of unwanted crossreactivity. Epitope mapping of four monoclonal anti-STh and six anti-STp antibodies, all of which neutralized both STh and STp, revealed that most epitopes appear to have at least one amino acid residue shared with guanylin or uroguanylin. Despite this, only one monoclonal antibody displayed demonstrable cross-reactivity to the endogenous peptides, suggesting that targeted mutations of a limited number of ST residues may be sufficient to obtain a safe ST-based vaccine.