China
Africa
Explore chapters and articles related to this topic
Neuropathogenesis of viral infections
Published in Avindra Nath, Joseph R. Berger, Clinical Neurovirology, 2020
Avindra Nath, Joseph R. Berger
Most microorganisms are known to produce toxic substances. For example, bacterial toxins include cholera toxin, botulinum toxin, tetanus toxoid, etc. Prion proteins have been studied extensively with regards to their neurotoxic properties. Similarly, viral products may also be toxic. Although virotoxins have been best characterized for HIV gene products, it is increasingly clear that several other viruses also produce toxic gene products (Table 2.5). For example, the rabies virus [53] envelope glycoprotein and the measles virus hemagglutinin glycoprotein [54] have sequence homology to snake venom neurotoxins and the fusion domain of influenza virus has a striking similarity to the neurotoxic domain of amyloid beta peptide [55]. A common theme emerges in these viruses, in that often it is the envelope and the transactivating viral genes that are toxic. These viral proteins may interact with neurons and glial cells to disrupt their function.
How can monoclonal antibodies be harnessed against neglected tropical diseases and other infectious diseases?
Published in Expert Opinion on Drug Discovery, 2019
Mushroom poisonings occur across tropical, subtropical, and temperate climates, but share some similar characteristics with animal envenomings and neglected tropical diseases and have thus been included in this review. About 5000 different species of mushrooms exist, with about 50 species being poisonous to humans [15]. In contrast to venom toxins that due to their size and proteinaceous nature are unable to be absorbed in the gastrointestinal tract, mushroom poisons comprise small oligopeptidic toxins that can be readily absorbed in the gastrointestinal tract and are thus toxic when ingested [91]. Most of the mushroom species involved in lethal poisonings are found in the genus Amanita, which produces amatoxins, phallotoxins, and virotoxins [99]. Of these toxins, the amatoxins are of highest medical concern, and they retain their potent hepatotoxicity even upon boiling. Their mode of action involves inhibition of the RNA polymerase II, responsible for transcription of mRNA [100]. Even today, the treatment options for mushroom poisonings caused by amatoxins remain inadequate, and severe cases of poisoning can necessitate liver transplantation [101–105]. Despite their small size, amatoxins may invoke an immune response, and researchers have reported the development of both IgG and Fab-based monoclonal antibodies using hybridoma technology [106]. Interestingly, when these two different antibody formats were assessed for their ability to neutralize amatoxins in a murine model, it was discovered that instead of neutralizing the toxins, both antibody types enhanced toxicity. Particularly, the Fab antibody was shown to dramatically enhance toxicity 50-fold, as the Fab antibody increased the accumulation of the toxin in the kidneys, causing major nephrotoxicity [106]. More than a decade ago, it was reported that attempts to use antibody-based therapies against mushroom poisonings had not been successful [15], and this finding remains the status quo. It is thus uncertain whether effective antibody-based therapeutics may ever find their way into the field of mushroom poisoning; however, the possibility cannot be entirely excluded. Some of the many recently developed advanced antibody formats, such as bispecifics and novel binding protein scaffolds, may offer improved or entirely different mechanisms of action and pharmacokinetics that might find their utility in mushroom poisoning therapy.