Comparative proteome analysis of the midgut of Rhipicephalus microplus (Acari: Ixodidae) strains with contrasting resistance to ivermectin reveals the activation of proteins involved in the detoxification metabolism

Ruiz‐May, Eliel; Álvarez-Sánchez, María Elizbeth; Aguilar-Tipacamú, Gabriela; Elizalde‐Contreras, José M.; Bojórquez‐Velázquez, Esaú; Zamora‐Briseño, Jesús Alejandro; Vázquez-Carrillo, Laura Isabel; López-Esparza, Areli

doi:10.1016/j.jprot.2022.104618

Cited by 5 publications

(7 citation statements)

References 53 publications

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“…A similar set of core genes such as, PgB03_g135 ( wapl-1 ), PgR024_g010 ( capg-2 ) and PgR027_g140 ( tln-1 ) were seen in the current study, suggesting a potentially conserved response mechanism across different nematode species to IVM exposure. Concurrently, were observed upregulation of core genes involved in protein synthesis and management of misfolded/unfolded proteins, congruent with the ORA results in this study and other studies [30, 31, 45, 46]. Interestingly, enrichment of these protein synthesis processes was also reported in unexposed IVM-susceptible and resistant H. contortus [31], suggesting that IVM exposure increases the magnitude of expression due to detoxification.…”

Section: Discussionsupporting

confidence: 91%

Gene co-expression network analysis reveal core responsive genes inParascaris univalenstissues following ivermectin exposure

Dube,

Delhomme,

Martin

et al. 2023

Preprint

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Anthelmintic resistance in equine parasiteParascaris univalens, compromises ivermectin (IVM) effectiveness and necessitates an in-depth understanding of its resistance mechanisms. Most research, primarily focused on holistic gene expression analyses, may overlook vital tissue-specific responses and often limit the scope of novel genes. This study leveraged gene co-expression network analysis to elucidate tissue-specific transcriptional responses and to identify core genes implicated in the IVM response inP. univalens. Adult worms (n=28) were exposed to 10-11M and 10-9M IVMin vitrofor 24 hours. RNA-sequencing examined transcriptional changes in the anterior end and intestine. Differential expression analysis revealed pronounced tissue differences, with the intestine exhibiting substantially more IVM-induced transcriptional activity. Gene co-expression network analysis identified seven modules significantly associated with the response to IVM. Within these, 219 core genes were detected, largely expressed in the intestinal tissue and spanning diverse biological processes with unspecific patterns. After 10-11M IVM, intestinal tissue core genes showed transcriptional suppression, cell cycle inhibition, and ribosomal alterations. Interestingly, genesPgR028_g047(sorb-1),PgB01_g200(gmap-1) andPgR046_g017(col-37&col-102) switched from downregulation at 10-11M to upregulation at 10-9M IVM. The 10-9M concentration induced expression of cuticle and membrane integrity core genes in the intestinal tissue. No clear core gene patterns were visible in the anterior end after 10-11M IVM. However, after 10-9M IVM, the anterior end mostly displayed downregulation, indicating disrupted transcriptional regulation. One interesting finding was the non-modular calcium-signaling gene,PgR047_g066 (gegf-1), which uniquely connected 71 genes across four modules. These genes were enriched for transmembrane signaling activity, suggesting thatPgR047_g066 (gegf-1)could have a key signaling role. By unveiling tissue-specific expression patterns and highlighting biological processes through unbiased core gene detection, this study reveals intricate IVM responses inP. univalens. These findings suggest alternative drug uptake of IVM and can guide functional validations to further IVM resistance mechanism understanding.Author summaryIn our study, we tackled the challenge of understanding how the equine roundwormParascaris univalenshas become resistant to ivermectin (IVM). We exposed adult worms in laboratory conditions to IVM and thereafter dissected two tissues, the frontal part and the intestine of the worm. We used gene networks and focused on how these two tissues respond at the genetic level to exposure of IVM. We discovered that the response to IVM is highly tissue-specific. The intestinal tissue, in particular, showed a much stronger reaction to the drug compared to the frontal part of the worm. We identified 219 key genes, mainly in the intestinal tissue, involved in various biological functions that play a crucial role in how the parasite deals with IVM. Interestingly, we found a decrease in gene activity leading to cellular disruptions at lower drug concentration, whereas genes responsible for maintaining the worm’s structural integrity were triggered at high concentration. One of our significant finding was the identification of,PgR047_g066 (gegf-1), which seems to act as a master regulator, coordinating the response of numerous other genes. This finding opens new avenues for understanding the complex ways in whichP. univalensrespond to drug treatment. Our research not only sheds light on the specific waysP. univalensresponds to IVM, but it also demonstrates the power of looking at gene networks to uncover new and important genes. These insights can be crucial for developing new strategies to combat drug resistance in parasites, a matter of great importance in both veterinary and human medicine.

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Section: Discussionsupporting

confidence: 91%

Gene co-expression network analysis reveal core responsive genes inParascaris univalenstissues following ivermectin exposure

Dube,

Delhomme,

Martin

et al. 2023

Preprint

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“…Again they found increased expression of ABC transporter genes, and increased susceptibility to ivermectin after the addition of cyclosporin A (Pohl et al 2011 ), which is a known inhibitor of ABC transporters. A similar response was observed in the midgut of ticks and in body lice after exposure to ivermectin (Yoon et al 2011 ; Ruiz-May et al 2022 ).…”

Section: Resultssupporting

confidence: 68%

“…Several studies have suggested that ivermectin resistance is associated with changes in ABC transporter gene expression, an efflux pump commonly associated with multi-resistance (Yoon et al 2011 ; Ruiz-May et al 2022 ; Gall et al 2018 ; Khangembam et al 2018 ; Kim et al 2018 ; Buss et al 2002 ; Pohl et al 2014 Cafarchia et al 2014 ; Pohl et al 2011 ). A large study that analysed 12,712 field-collected tick samples and compared them to 6639 susceptible samples assessed the relationship between ivermectin resistance and the expression of several different detoxification genes (Gall et al 2018 ).…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

“…Cytochrome (CYP) P450 has also been reported to have a role in ivermectin resistance in a number of studies (Ruiz-May et al 2022 ; Gall et al 2018 ; Kim et al 2018 ; Shakya et al 2022 ; Chaccour et al 2017 ; Nicolas et al 2021 ). Two transcriptomic analyses of ivermectin-resistant ticks compared to susceptible ticks found that cytochrome P450 had an important role in ivermectin resistance in ticks (Ruiz-May et al 2022 ; Gall et al 2018 ). Shakya et al assessed the effect of adding synergists to resistant tick populations and found that there was a significant positive relationship between the resistance factor and the synergy factor with PBO and VER, suggesting that cytochrome P450 is involved in ivermectin resistance (Shakya et al 2022 ).…”

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

Ivermectin resistance mechanisms in ectoparasites: a scoping review

Furnival-Adams,

Kiuru,

Sagna

et al. 2024

Parasitol Res

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Ivermectin mass drug administration has been used for decades to target human and veterinary ectoparasites, and is currently being considered for use against malaria vectors. Although there have been few reports of resistance to date in human ectoparasites, we must anticipate the development of resistance in mosquitoes in the future. Hence, through this review, we mapped the existing evidence on ivermectin resistance mechanisms in human ectoparasites. A search was conducted on the 8th November 2023 through databases, PubMed, Web of Science, and Google Scholar, using terms related to ivermectin, human and veterinary ectoparasites, and resistance. Abstracts (5893) were screened by JFA and CK. Data on the study organism, the type of resistance, the analysis methods, and, where applicable, the gene loci of interest were extracted from the studies. Details of the methodology and results of each study were summarised narratively and in a table. Eighteen studies were identified describing ivermectin resistance in ectoparasites. Two studies described target site resistance; and 16 studies reported metabolic resistance and/or changes in efflux pump expression. The studies investigated genetic mutations in resistant organisms, detoxification, and efflux pump expression in resistant versus susceptible organisms, and the effect of synergists on mortality or detoxification enzyme/efflux pump transcription. To date, very few studies have been conducted examining the mechanisms of ivermectin resistance in ectoparasites, with only two on Anopheles spp. Of the existing studies, most examined detoxification and efflux pump gene expression, and only two studies in lice investigated target-site resistance. Further research in this field should be encouraged, to allow for close monitoring in ivermectin MDA programmes, and the development of resistance mitigation strategies. Graphical Abstract

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The ovaries of ivermectin-resistant Rhipicephalus microplus strains display proteomic adaptations involving the induction of xenobiotic detoxification and structural remodeling mechanisms

Álvarez-Sánchez

Ruiz‐May

Aguilar-Tipacamú

et al. 2023

Journal of Proteomics

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Comparative proteome analysis of the midgut of Rhipicephalus microplus (Acari: Ixodidae) strains with contrasting resistance to ivermectin reveals the activation of proteins involved in the detoxification metabolism

Cited by 5 publications

References 53 publications

Gene co-expression network analysis reveal core responsive genes inParascaris univalenstissues following ivermectin exposure

Gene co-expression network analysis reveal core responsive genes inParascaris univalenstissues following ivermectin exposure

Ivermectin resistance mechanisms in ectoparasites: a scoping review

The ovaries of ivermectin-resistant Rhipicephalus microplus strains display proteomic adaptations involving the induction of xenobiotic detoxification and structural remodeling mechanisms

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