Metabolic Deficiencies Underlie Reduced Plasmacytoid Dendritic Cell IFN-I Production following Viral Infection. Metabolic Deficiencies Underlie Reduced Plasmacytoid Dendritic Cell IFN-I Production following Viral Infection

Type I Inter ferons (IFN-I) are central to host protection against viral infections, with plasmacytoid dendritic cells (pDC) being the most significant source, yet pDCs lose their exceptional IFN-I production capacity following an initial burst of IFN-I, resulting in susceptibility to secondary infections. The underlying mechanisms of these dynamics are not well understood. Here we find that viral infection reduces the capacity of pDCs to engage both oxidative and glycolytic metabolism. Mechanistically, we identify lactate dehydrogenase B (LDHB) as a positive regulator of pDC IFN-I production in mice and humans; meanwhile, LDHB deficiency is associated with suppressed IFN-I production, pDC metabolic capacity, and viral control following infection. In addition, preservation of LDHB expression is sufficient to partially retain the function of otherwise exhausted pDCs, both in vitro and in vivo. Furthermore, restoring LDHB in vivo in pDCs from infected mice increases IFNAR-dependent, infection-associated pathology. Our work identifies a mechanism for balancing immunity and pathology during viral infections, while also providing insight into the highly preserved infection-driven pDC inhibition. Overall design: Mixed bone marrow chimeras were infected with LCMV Cl13, and WT or TLR7ko pDC were isolated from the spleens of these mice at day 8 post infection prior to RNA extraction. 2 independent biological replicates were performed.

I型干扰素（Type I Interferons, IFN-I）是宿主抵御病毒感染的核心免疫保护因子，浆细胞样树突状细胞（plasmacytoid dendritic cells, pDC）是其最主要的产生来源。然而，pDC在经历初始爆发性的IFN-I分泌后，会丧失其卓越的IFN-I产生能力，进而导致机体对继发感染的易感性升高。目前学界对这类动态变化的潜在分子机制尚未完全阐明。本研究发现，病毒感染会削弱pDC同时激活氧化代谢与糖酵解代谢的能力。机制层面，我们鉴定出乳酸脱氢酶B（lactate dehydrogenase B, LDHB）在小鼠与人类体内均为pDC产生IFN-I的正向调控因子；同时，LDHB缺陷会导致感染后IFN-I产生受抑、pDC代谢能力下降以及病毒清除能力受损。此外，无论是在体外还是体内实验中，维持LDHB的表达足以部分恢复原本耗竭的pDC功能。进一步研究显示，在感染小鼠的pDC中恢复LDHB的体内表达，会加重依赖I型干扰素受体（IFNAR）的感染相关病理损伤。本研究揭示了病毒感染过程中平衡免疫应答与病理损伤的潜在机制，同时为高度保守的感染诱导性pDC抑制现象提供了新的见解。总体实验设计：将混合骨髓嵌合小鼠感染淋巴细胞脉络丛脑膜炎病毒克隆13株（LCMV Cl13），于感染后第8天从这些小鼠的脾脏中分离野生型（WT）或TLR7敲除（TLR7ko）的pDC，随后进行RNA提取。本实验共完成2次独立生物学重复。