Data_Sheet_4_L-Ascorbic Acid Shapes Bovine Pasteurella multocida Serogroup A Infection.DOCX

Bovine Pasteurella multocida serogroup A (bovine PmA) is one of the most important pathogens causing fatal pneumonia in cattle. However, it is largely unknown how nutrition shapes bovine PmA infection. Here, we discovered that the infected lung held the highest bacterial density than other tissues during infection. By screening the different metabolites between high (lung)- and low (liver)-bacterial density tissues, the present work revealed that L-ascorbic acid and L-aspartic acid directly influenced bovine P. multocida growth. Interestingly, L-ascorbic acid, which is expressed at higher levels in the infected livers, inhibited bovine PmA growth as well as virulence factor expression and promoted macrophage bactericidal activity in vitro. In addition, ascorbic acid synthesis was repressed upon bovine PmA infection, and supplementation with exogenous L-ascorbic acid significantly reduced the bacterial burden of the infected lungs and mouse mortality. Collectively, our study has profiled the metabolite difference of the murine lung and liver during bovine PmA infection. The screened L-ascorbic acid showed repression of bovine PmA growth and virulence expression in vitro and supplementation could significantly increase the survival rate of mice and reduce the bacterial load in vivo, which implied that L-ascorbic acid could serve as a potential protective agent for bovine PmA infection in clinic.

多杀性巴氏杆菌A血清群牛源分离株（Bovine Pasteurella multocida serogroup A，以下简称牛源PmA）是引发牛致死性肺炎的关键致病菌之一。然而目前学界对营养环境如何调控牛源PmA感染的分子机制仍知之甚少。本研究首先观察到，感染进程中宿主肺部的细菌载量显著高于其他组织。通过对比细菌载量较高的肺部与载量较低的肝脏组织的代谢物谱差异，本研究揭示L-抗坏血酸（L-ascorbic acid）与L-天冬氨酸（L-aspartic acid）可直接影响牛源多杀性巴氏杆菌的生长。值得注意的是，尽管L-抗坏血酸在感染肝脏中的表达水平更高，其仍可在体外抑制牛源PmA的生长与毒力因子表达，并增强巨噬细胞的杀菌活性。此外，牛源PmA感染会抑制宿主自身的抗坏血酸合成通路；而外源性补充L-抗坏血酸可显著降低感染小鼠肺部的细菌负荷，并降低小鼠死亡率。综上，本研究刻画了牛源PmA感染过程中小鼠肺部与肝脏的代谢物差异谱。所筛选得到的L-抗坏血酸可在体外抑制牛源PmA的生长与毒力表达，而体内补充该物质可显著提升小鼠存活率并降低细菌载量，提示L-抗坏血酸有望成为临床防治牛源PmA感染的潜在保护剂。