Neutralization of cholera toxin with nanoparticle decoys for treatment of cholera

Abstract

Diarrheal diseases are a major cause of morbidity and mortality worldwide. In many cases, antibiotic therapy is either ineffective or not recommended due to concerns about emergence of resistance. The pathogenesis of several of the most prevalent infections, including cholera and enteroxigenic Escherichia coli, is dominated by enterotoxins produced by lumen-dwelling pathogens before clearance by intestinal defenses. Toxins gain access to the host through critical host receptors, making these receptors attractive targets for alternative antimicrobial strategies that do not rely on conventional antibiotics. Here, we developed a new nanotechnology strategy as a countermeasure against cholera, one of the most important and prevalent toxin-mediated enteric infections. The key host receptor for cholera toxin, monosialotetrahexosylganglioside (GM1), was coated onto the surface of polymeric nanoparticles. The resulting GM1-polymer hybrid nanoparticles were shown to function as toxin decoys by selectively and stably binding cholera toxin, and neutralizing its actions on epithelial cells in vitro and in vivo. Furthermore, the GM1-coated nanoparticle decoys attenuated epithelial 3’,5’-cyclic adenosine monophosphate production and fluid responses to infection with live Vibrio cholera in cell culture and a murine infection model. Together, these studies illustrate that the new nanotechnology-based platform can be employed as a non-traditional antimicrobial strategy for the management of enteric infections with enterotoxin-producing pathogens.

Inorganic and Polymeric Nanoparticles for Human Viral and Bacterial Infections Prevention and Treatment

“…The main inconvenient of this approach would be the possible threat which ZnO NPs would suppose for the environment [ 107 ]. Another current work has demonstrated that GM1 ganglioside-coated PLGA hybrid NPs able to recruit cholera toxin and impede its interaction with its receptor in enterocytes by using a murine in vivo model [ 108 ]. The biodegradable character of PLGA NPs made them more clinically applicable and harmless to the environment.…”

State-of-the-art polymeric nanoparticles as promising therapeutic tools against human bacterial infections

“…As happens with other bacterial infections, the appearance of MDR has promoted an urgent need to develop alternative treatments against V. cholera . In that sense, Das and colleges designed surface modified PLGA NPs with PEG and GM1, a key host receptor for choler toxin, as a recruitment and clearance tool of enterotoxin [ 84 ]. Obtained results demonstrated that these PNPs are able to selectively and stably binding cholera toxin, thus neutralizing its actions.…”

Bioinspired and Biomimetic Nanotherapies for the Treatment of Infectious Diseases

“…For example, synthetic nanoparticles based on copolymers of acrylic acid, N-tert-butylacrylamide, N-isopropylacrylamide, and N,N′-methylenebisacrylamide could effectively capture and neutralize the toxicity of a peptide toxin melittin by electrostatic and hydrophobic interactions (Hoshino et al, 2012; Yoshimatsu et al, 2015). By coating monosialotetrahexosylganglioside (GM1), a key host receptor for cholera toxin, on the surface of PLGA nanoparticles, an effective toxin-neutralizing nanoplatform was obtained, which can selectively neutralize the effects of cholera toxin on epithelial cells (Das et al, 2018). Moreover, the GM1-coated nanoparticle decoys effectively attenuated intestinal secretory responses of live V. cholerae in a murine infection model.…”