美国圣路易斯华盛顿大学医学院Sharon Celeste Morley研究小组发现，一种新的辅酶Q6遗传变异增加对肺炎球菌病的易感性。该项研究成果于2024年11月4日在线发表在《自然—免疫学》杂志上。

研究人员表示，急性下呼吸道感染（ALRI）仍然是全球儿童死亡的主要原因，迫切需要在预防和治疗方面进行创新。巴布亚新几内亚（PNG）的儿童由于肺炎球菌引起的ALRI，经历了严重的发病率。由于演化分化，PNG的人群表现出显著的遗传变异和多样性。

为了解决PNG儿童未满足的健康需求，研究人员测试了是否存在遗传变异导致ALRI的发病率增加。对一个初步儿童队列进行全外显子组测序，研究人员发现ALRI病例中存在辅酶Q6（COQ6）中的新型单核苷酸变异（SNV）的纯合子。COQ6编码一种线粒体酶，参与辅酶Q的生物合成，辅酶Q是电子传递链中的电子受体。

SNV纯合子与ALRI的显著关联在独立的ALRI队列中得到了重复验证（P=0.036）。纯合鼠品种Coq6在肺炎球菌肺部感染后表现出较高的死亡率，从而确认了因果关系。骨髓嵌合小鼠进一步表明，变异Coq6在受体（非造血）组织中的表达导致了死亡率增加。变异Coq6维持了辅酶Q的生物合成，并在肺炎球菌挑战后加速了代谢重塑。

这一COQ6变异的发现为PNG地区肺炎易感性提供了遗传基础，并揭示了COQ6酶在调节炎症介导的代谢重塑中的新角色。

附：英文原文

Title: Novel coenzyme Q6 genetic variant increases susceptibility to pneumococcal disease

Author: Walker, Emma C., Javati, Sarah, Todd, Elizabeth M., Matlam, John-Paul, Lin, Xue, Bryant, Michelle, Krone, Emily, Ramani, Rashmi, Chandra, Pallavi, Green, Taylor P., Anaya, Edgar P., Zhou, Julie Y., Alexander, Katherine A., Tong, R. Spencer, Yuasi, Lapule, Boluarte, Sebastian, Yang, Fan, Greenberg, Lina, Nerbonne, Jeanne M., Greenberg, Michael J., Clemens, Regina A., Philips, Jennifer A., Wilson, Leslie D., Halabi, Carmen M., DeBosch, Brian J., Blyth, Christopher C., Druley, Todd E., Kazura, James W., Pomat, William S., Morley, Sharon Celeste

Issue&Volume: 2024-11-04

Abstract: Acute lower respiratory tract infection (ALRI) remains a major worldwide cause of childhood mortality, compelling innovation in prevention and treatment. Children in Papua New Guinea (PNG) experience profound morbidity from ALRI caused by Streptococcus pneumoniae. As a result of evolutionary divergence, the human PNG population exhibits profound genetic variation and diversity. To address unmet health needs of children in PNG, we tested whether genetic variants increased ALRI morbidity. Whole-exome sequencing of a pilot child cohort identified homozygosity for a novel single-nucleotide variant (SNV) in coenzyme Q6 (COQ6) in cases with ALRI. COQ6 encodes a mitochondrial enzyme essential for biosynthesis of ubiquinone, an electron acceptor in the electron transport chain. A significant association of SNV homozygosity with ALRI was replicated in an independent ALRI cohort (P=0.036). Mice homozygous for homologous mouse variant Coq6 exhibited increased mortality after pneumococcal lung infection, confirming causality. Bone marrow chimeric mice further revealed that expression of variant Coq6 in recipient (that is, nonhematopoietic) tissues conferred increased mortality. Variant Coq6 maintained ubiquinone biosynthesis, while accelerating metabolic remodeling after pneumococcal challenge. Identification of this COQ6 variant provides a genetic basis for increased pneumonia susceptibility in PNG and establishes a previously unrecognized role for the enzyme COQ6 in regulating inflammatory-mediated metabolic remodeling.

DOI: 10.1038/s41590-024-01998-4

Source: https://www.nature.com/articles/s41590-024-01998-4