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.

急性下呼吸道感染 （ALRI） 仍然是世界儿童死亡的主要原因，这迫使预防和治疗方面的创新。巴布亚新几内亚 （PNG） 的儿童因肺炎链球菌引起的 ALRI 发病率很高。由于进化分化，人类 PNG 种群表现出深刻的遗传变异和多样性。为了解决巴布亚新几内亚儿童未满足的健康需求，我们测试了基因变异是否会增加 ALRI 发病率。在患有 ALRI 的病例中，试验儿童队列的全外显子组测序确定了辅酶 Q6 （COQ6） 中一种新的单核苷酸变体 （SNV） 的纯合性。辅酶 Q6 编码一种线粒体酶，这种酶对泛醌的生物合成至关重要，泛醌是电子传递链中的电子受体。SNV 纯合性与 ALRI 的显著关联在独立的 ALRI 队列中复制 （P = 0.036）。同源小鼠变体 Coq6 的纯合子小鼠在肺炎球菌肺部感染后表现出死亡率增加，证实了因果关系。骨髓嵌合小鼠进一步揭示，受体（即非造血）组织中变体 Coq6 的表达导致死亡率增加。变体 Coq6 维持泛醌生物合成，同时加速肺炎球菌攻击后的代谢重塑。这种 COQ6 变体的鉴定为巴布亚新几内亚肺炎易感性增加提供了遗传基础，并确定了 COQ6 酶在调节炎症介导的代谢重塑中以前未被认识的作用。