PDF(Pubmed)
Abstract：
Anthelmintic resistance in equine parasite Parascaris 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 in P. univalens. Adult worms (n = 28) were exposed to 10-11 M and 10-9 M IVM in vitro for 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 10-11 M IVM, intestinal tissue core genes showed transcriptional suppression, cell cycle inhibition, and ribosomal alterations. Interestingly, genes PgR028_g047 (sorb-1), PgB01_g200 (gmap-1) and PgR046_g017 (col-37 & col-102) switched from downregulation at 10-11 M to upregulation at 10-9 M IVM. The 10-9 M 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 10-11 M IVM. However, after 10-9 M 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 that PgR047_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 in P. univalens. These findings suggest alternative drug uptake of IVM and can guide functional validations to further IVM resistance mechanism understanding.
摘要：
马寄生虫的驱虫抗性，损害伊维菌素（IVM）的有效性，有必要深入了解其抗性机制。大多数研究,主要集中在整体基因表达分析，可能会忽略重要的组织特异性反应，并经常限制新基因的范围。这项研究利用基因共表达网络分析来阐明组织特异性转录反应，并鉴定参与单戊菌IVM反应的核心基因。将成虫(n=28)在体外暴露于10-11M和10-9M的IVM24小时。RNA测序检查了前端和肠道的转录变化。差异表达分析显示明显的组织差异，肠表现出明显更多的IVM诱导的转录活性。基因共表达网络分析确定了与对IVM的反应显着相关的七个模块。在这些之内,共检测到219个核心基因,主要在肠组织中表达，并以非特异性模式跨越不同的生物过程。在10-11MIVM之后，肠组织核心基因显示转录抑制，细胞周期抑制，和核糖体改变。有趣的是,基因PgR028_g047（sorb-1），PgB01_g200（gmap-1）和PgR046_g017（col-37和col-102）从10-11M的下调切换到10-9MIVM的上调。10-9μM浓度诱导肠组织中表皮和膜完整性核心基因的表达。在10-11MIVM后，前端没有明显的核心基因模式。然而,在10-9MIVM之后，前端大多显示下调，表明转录调节中断。一个有趣的发现是非模块化钙信号基因，PgR047_g066(gegf-1),它独特地连接了四个模块中的71个基因。这些基因富含跨膜信号活性，这表明PgR047_g066(gegf-1)可能具有关键的信号作用。通过无偏核心基因检测揭示组织特异性表达模式并突出生物学过程，这项研究揭示了单戊菌中复杂的IVM反应。这些发现表明IVM的替代药物摄取，并可以指导功能验证以进一步了解IVM耐药机制。
