Key Laboratory of Animal Genetics, Breeding and Reproduction, Ministry of Agriculture & National Engineering Laboratory for Animal Breeding, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China.
BMC Genomics. 2024 Nov 7;25(1):1051. doi: 10.1186/s12864-024-10895-x.
Staphylococcus aureus (S. aureus) mastitis results in economic losses during dairy production. Understanding the biological progression of bovine S. aureus mastitis is vital for its prevention. Lipoteichoic acid is a key virulence factor of S. aureus (aLTA), but the main biological pathways involved in its effect on bovine mammary epithetionallial cells (Mac-T) apoptosis and necrosis have not been fully explored. Folic acid (FA) has anti-inflammatory and anti-apoptotic effects. However, the role of FA in mediating the effects of aLTA on apoptosis and necrosis remains unknown.
We found that low concentration of aLTA inhibited apoptosis and necrosis and that high concentration promoted the apoptosis and necrosis of Mac-T. FA pretreatment alleviated high concentration of aLTA induced apoptosis. Through transcriptomic analysis, we found that nuclear receptor subfamily 4 group A (NR4A), which alters the expression of downstream genes involved in apoptosis, proliferation, and inflammation, decreased under stimulation with a low concentration of aLTA and increased under stimulation with a high concentration of aLTA. Under stimulation with a high concentration of aLTA, the expression of the NR4A subfamily could be inhibited by FA. The results showed that aLTA may affect apoptosis and necrosis through the NR4A subfamily by targeting genes involved in bacterial invasion of epithelial cells, the IL-17 signaling pathway, DNA replication, longevity regulation, the cell cycle, and tight junction pathways. We further found that the expression trends of NR4A1 and the target genes of the NR4A subfamily (PTGS2, ESPL1, MCM5, and BUB1B) in the blood of healthy cows (Healthy), subclinical mastitis cows (SCM), and SCM supplemented with FA (SCM_FA) were consistent with those observed at the cellular level in this study.
Our study revealed that low and high concentrations of aLTA have opposite effects on apoptosis and necrosis of Mac-T and that FA can alleviate the apoptosis induced by high concentration of aLTA. Transcriptome analysis revealed that the NR4A subfamily play a role in the ability of FA to alleviate the apoptosis and necrosis induced by high concentration of aLTA.
金黄色葡萄球菌（S. aureus）乳腺炎会导致奶牛养殖业的经济损失。了解奶牛金黄色葡萄球菌乳腺炎的生物学进展对于其预防至关重要。脂磷壁酸（LTA）是金黄色葡萄球菌（aLTA）的关键毒力因子，但它对奶牛乳腺上皮细胞（Mac-T）凋亡和坏死的主要生物学途径尚未被充分探索。叶酸（FA）具有抗炎和抗凋亡作用。然而，FA 在介导 aLTA 对凋亡和坏死的影响中的作用尚不清楚。
我们发现低浓度的 aLTA 抑制凋亡和坏死，而高浓度促进 Mac-T 的凋亡和坏死。FA 预处理减轻了高浓度 aLTA 诱导的凋亡。通过转录组分析，我们发现核受体亚家族 4 组 A（NR4A）改变了与凋亡、增殖和炎症相关的下游基因的表达，在低浓度 aLTA 刺激下减少，在高浓度 aLTA 刺激下增加。在高浓度 aLTA 的刺激下，FA 可以抑制 NR4A 亚家族的表达。结果表明，aLTA 可能通过靶向参与细菌侵袭上皮细胞、IL-17 信号通路、DNA 复制、长寿调节、细胞周期和紧密连接通路的基因，通过 NR4A 亚家族影响凋亡和坏死。我们进一步发现，健康奶牛（Healthy）、亚临床乳腺炎奶牛（SCM）和补充 FA 的 SCM（SCM_FA）血液中 NR4A1 和 NR4A 亚家族靶基因（PTGS2、ESPL1、MCM5 和 BUB1B）的表达趋势与本研究中细胞水平观察到的一致。
本研究表明，低浓度和高浓度的 aLTA 对 Mac-T 的凋亡和坏死有相反的影响，FA 可以减轻高浓度 aLTA 诱导的凋亡。转录组分析表明，NR4A 亚家族在 FA 减轻高浓度 aLTA 诱导的凋亡和坏死的能力中发挥作用。
