SALUVET, Animal Health Department, Faculty of Veterinary Sciences, Complutense University of Madrid, Madrid, Spain.
Department of Biochemistry and Molecular Biology, Faculty of Veterinary Sciences, Complutense University of Madrid, Madrid, Spain.
Front Immunol. 2023 Jul 14;14:1198609. doi: 10.3389/fimmu.2023.1198609. eCollection 2023.
Research on bovine neosporosis has achieved relevant milestones, but the mechanisms underlying the occurrence of foetal death or protection against foetal death remain unclear. In a recent study, placentas from heifers challenged with the high-virulence isolate Nc-Spain7 exhibited focal necrosis and inflammatory infiltrates as soon as 10 days post-infection (dpi), although parasite detection was minimal. These lesions were more frequent at 20 dpi, coinciding with higher rates of parasite detection and the occurrence of foetal death in some animals. In contrast, such lesions were not observed in placentas from animals infected with the low-virulence isolate Nc-Spain1H, where the parasite was detected only in placenta from one animal at 20 dpi. This work aimed to study which mechanisms are triggered in the placentas (caruncles and cotyledons) of these pregnant heifers at early stages of infection (10 and 20 dpi) through whole-transcriptome analysis. In caruncles, infection with the high-virulence isolate provoked a strong proinflammatory response at 10 dpi. This effect was not observed in heifers infected with the low-virulence isolate, where IL-6/JAK/STAT3 signalling and TNF-alpha signalling NF-κB pathways were down-regulated. Interestingly, the expression of E2F target genes, related to restraining the inflammatory response, was higher in these animals. At 20 dpi, more pronounced proinflammatory gene signatures were detectable in heifers infected with the high-virulence isolate, being more intense in heifers carrying dead fetuses. However, the low-virulence isolate continued without activating the proinflammatory response. In cotyledons, the response to infection with the high-virulence isolate was similar to that observed in caruncles; however, the low-virulence isolate induced mild proinflammatory signals at 20 dpi. Finally, a deconvolutional analysis of gene signatures from both placentome tissues revealed a markedly higher fraction of activated natural killers, M1 macrophages and CD8+ T cells for the high-virulence isolate. Therefore, our transcriptomic analysis supports the hypothesis that an intense immune response probably triggered by parasite multiplication could be a key contributor to abortion. Further studies are required to determine the parasite effectors that govern the distinct interactions of high- and low-virulence isolates with the host, which could help elucidate the molecular processes underlying the pathogenesis of neosporosis in cattle.
牛新孢子虫病的研究已经取得了相关的里程碑，但导致胎儿死亡或防止胎儿死亡的机制仍不清楚。在最近的一项研究中，用高毒力分离株 Nc-Spain7 攻毒的小母牛的胎盘在感染后 10 天（dpi）即可观察到局灶性坏死和炎症浸润，尽管寄生虫检测很少。这些病变在 20 dpi 时更为常见，此时寄生虫检测率更高，并且一些动物发生了胎儿死亡。相比之下，用低毒力分离株 Nc-Spain1H 感染的动物的胎盘没有观察到这种病变，在 20 dpi 时仅在一头动物的胎盘上检测到寄生虫。本研究旨在通过全转录组分析研究在感染早期（10 和 20 dpi），这些怀孕小母牛的胎盘（caruncles 和 cotyledons）中触发了哪些机制。在 caruncles 中，高毒力分离株的感染在 10 dpi 时引发强烈的促炎反应。用低毒力分离株感染的小母牛则没有观察到这种反应，在这些动物中，IL-6/JAK/STAT3 信号和 TNF-α信号转导 NF-κB 途径被下调。有趣的是，与抑制炎症反应相关的 E2F 靶基因的表达在这些动物中更高。在 20 dpi 时，用高毒力分离株感染的小母牛中可检测到更明显的促炎基因特征，在携带死胎的小母牛中更为强烈。然而，低毒力分离株继续不激活促炎反应。在 cotyledons 中，高毒力分离株感染的反应与 caruncles 中观察到的反应相似；然而，低毒力分离株在 20 dpi 时诱导轻度促炎信号。最后，对两种胎盘组织的基因特征进行反卷积分析显示，高毒力分离株的激活自然杀伤细胞、M1 巨噬细胞和 CD8+T 细胞的比例明显更高。因此，我们的转录组分析支持这样一种假设，即由寄生虫增殖引发的强烈免疫反应可能是导致流产的关键因素。还需要进一步的研究来确定控制高毒力和低毒力分离株与宿主不同相互作用的寄生虫效应子，这有助于阐明牛新孢子虫病发病机制的分子过程。
