Navarro León Alejandra Isabel, Alonso-Hearn Marta, Muñoz Marta, Iglesias Natalia, Badia-Bringué Gerard, Iglesias Tania, Balseiro Ana, Casais Rosa
Center for Animal Biotechnology, Servicio Regional de Investigación y Desarrollo Agroalimentario (SERIDA), 33394 Deva, Spain.
Animal Health Department, NEIKER, Basque Institute for Agricultural Research and Development, Basque Research and Technology Alliance (BRTA), 48160 Alava, Spain.
Animals (Basel). 2025 Mar 31;15(7):1012. doi: 10.3390/ani15071012.
Summary-data-based Mendelian randomization (SMR) analysis identified a novel cis-expression quantitative loci (cis-eQTL) associated with the upregulation of the expression of the early growth response factor 4 (EGR4) gene in animals with paratuberculosis (PTB)-associated multifocal lesions, which has been suggested to be modulating the NF-kβ-induced proinflammatory immune response to subsp. (Map) infection. To confirm these findings and to study the role of EGR4 expression in PTB resilience, the number of EGR4-expressing cells were analysed in paraffin-fixed gut tissues and regional lymph nodes of naturally Map-infected Holstein Friesian cows with focal, multifocal (subclinical and clinical), and diffuse lesions (intermediate and multibacillary), and in controls without lesions by quantitative anti-EGR4 immunohistochemistry. Subclinical animals with multifocal lesions showed a significantly higher number of EGR4-positive cells and were sacrificed at a significantly older average age than the remaining groups ( < 0.001 in all cases). We hypothesize that EGR4 could be mitigating the negative impact of Map infection on host clinical status through its involvement in three molecular mechanisms that promote resilience: (i) limiting NF-kβ-mediated proinflammatory responses, (ii) controlling tissue damage, acting as a brake on T-cell proliferation and cytokine production, and (iii) favouring tissue repair through interaction with epidermal growth factor receptor (EGFR).
基于汇总数据的孟德尔随机化（SMR）分析确定了一个新的顺式表达定量位点（cis-eQTL），该位点与患有副结核病（PTB）相关多灶性病变的动物中早期生长反应因子4（EGR4）基因表达上调有关，有人认为该基因在调节对副结核分枝杆菌亚种（Map）感染的NF-kβ诱导的促炎免疫反应。为了证实这些发现并研究EGR4表达在PTB恢复力中的作用，通过定量抗EGR4免疫组织化学分析了自然感染Map的荷斯坦弗里生奶牛石蜡固定肠道组织和区域淋巴结中表达EGR4的细胞数量，这些奶牛有局灶性、多灶性（亚临床和临床）和弥漫性病变（中度和多菌型），并与无病变的对照组进行比较。具有多灶性病变的亚临床动物显示EGR4阳性细胞数量显著更多，并且牺牲时的平均年龄显著大于其余组（所有情况下P<0.001）。我们假设EGR4可能通过参与促进恢复力的三种分子机制来减轻Map感染对宿主临床状态的负面影响：（i）限制NF-kβ介导的促炎反应；（ii）控制组织损伤，作为T细胞增殖和细胞因子产生的制动器；（iii）通过与表皮生长因子受体（EGFR）相互作用促进组织修复。
