PRRSV调控猪肺泡巨噬细胞LXR-胆固醇代谢轴促进副猪嗜血杆菌继发感染的分子机制

猪繁殖与呼吸综合征病毒（PRRSV）和副猪嗜血杆菌（HPS）是严重危害养猪业发展的重要病原，PRRSV感染促进HPS继发感染并导致更高的死亡率，其作用机制尚不清楚。猪肺泡巨噬细胞（PAM）是PRRSV的靶细胞，肝X受体（LXR）-胆固醇代谢轴是调控巨噬细胞抵御病原感染的重要通路。前期研究发现LXR激活显著抑制PRRSV复制和HPS感染，而PRRSV感染下调LXR蛋白表达，引起胆固醇累积，加重HPS感染，提示PRRSV调控LXR-胆固醇代谢轴干扰PAM吞噬杀伤HPS。本课题将在此基础上，运用体内和体外两个感染模型，明确LXR调控胆固醇代谢抑制PRRSV和HPS感染的作用，解析PRRSV下调LXR蛋白表达调控胆固醇代谢的关键蛋白，揭示PRRSV拮抗LXR-胆固醇代谢通路，干扰吞噬体成熟，抑制PAM杀伤HPS的机制。本研究将阐明PRRSV促进HPS继发感染的机制，为疫病混合感染的防治提供新思路。

Porcine reproductive and respiratory syndrome virus (PRRSV) and haemophilus.parasuis (HPS) are the most important pathogens that seriously impair the development of pig industry in China. Several studies report that PRRSV infection can promote HPS proliferation and lead to higher mortality, but the mechanism is still not clear. Porcine alveolar macrophages (PAMs), the target cells of PRRSV infection, play a key role in inhibiting pathogens infection of the lungs. The LXR-cholesterol metabolism axis is an important pathway regulating macrophages against pathogenic infection. Our previous study found that LXR activation significantly inhibited the replication of PRRSV, promoted PAM to kill HPS. However, the infection of PRRSV could down-regulate of LXR expression at protein level in PAM cells and resulted in elevated intracellular cholesterol levels and more serious HPS infection. These evidences suggest that PRRSV infection disrupts the cholesterol homeostasis to promote HPS survival in PAM cells. On the basis of this study, we will clarify the inhibitory effect of LXR on PRRSV and HPS infection by regulating cholesterol metabolism using infection model in vivo and in vitro. Then we will elucidate the key protein of PRRSV down-regulating LXR protein expression. At last, we will reveal the mechanism that PRRSV antagonizes LXR-cholesterol pathway to induce accumulation of intracellular cholesterol, impairs phagosome maturation and supresses PAM to kill HPS. These studies will not only clearly explain how PRRSV promotes the proliferation and secondary infection of HPS, but also provide new insights into the prevention and treatment of mixed infections.