Caracterização da resistência ao albendazol em uma cepa de Ancylostoma ceylanicum selecionada em modelo experimental: integração de abordagens fenotípicas e genotípicas
Year: 2022
Type: dissertation
Abstract: Geohelminths represent a serious problem for human and animal health in different parts of the world. The zoonotic nematode that infects canids and felids, Ancylostoma ceylanicum, has been highly endemic among humans, comprising the second most common hookworm species in many parts of the world. One of the ways indicated by the World Health Organization (WHO) as a strategy to control geohelminths is the periodic mass treatment with benzimidazole compounds. However, this strategy leads to the establishment of treatment-resistant strains in several nematodes, through the selection of genotypes with a profile for resistance to this line of drugs. In ruminant nematodes, the relationship between resistance to benzimidazoles and single nucleotide polymorphisms (SNPs) in codons 167, 198 and 200 of the β-tubulin isotype 1 gene is well established. However, there is no confirmation of this mechanism for nematodes that infect humans. and canids. The objective of this work was to select by selective pressure, using the drug albendazole, a resistant strain of A. ceylanicum in an experimental model and subsequent phenotypic and genotypic characterization, as well as evaluating the presence of cross-resistance between the selected strain and drugs from other classes. The strain was successfully selected through serial passages of infection in hamsters, with increasing doses of the drug, followed by treatment. Sequencing of the regions of codons 167, 198 and 200 of the isotype 1 β-tubulin gene demonstrated a highly significant correlation between the frequency of the SNP at codon 198 and the increase in drug concentration. Sequencing also revealed an increase in the frequency of the mutated allele at codon 198 directly proportional to the number of passages of the resistant strain, with increasing drug concentration. Also with this increase in the drug dose, a new SNP was detected for codon 200, already described for ruminant parasites, but never described for nematodes infecting humans. Tests were performed to verify cross-resistance, using the drugs albendazole, mebendazole, ivermectin and nitazoxanide. The results found only demonstrated the existence of lateral resistance among the analyzed drugs. In the comparison of infections between the susceptible and resistant strains to albendazole, no significant difference was observed in the pathogenic aspects between the two groups, but the number of worms recovered was higher in the wild strain, revealing its better adaptation to the host. The total length of the worms of the resistant strain was greater in relation to the wild strain, a result probably due to the greater number of worms present in the host, over the wild strain. The results found here strongly suggest the association of alterations in codons of the gene encoding the Beta-tubulin protein with the mechanisms of resistance to benzimidazoles in hookworms, as has already been demonstrated for ruminant parasites.
Author: Celi da Silva Medeiros
Language: Portuguese
Subfield: Parasitology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7119303181