Novel coenzyme Q6 genetic variant increases susceptibility to pneumococcal disease

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.

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Publication Details

Journal
Nature Immunology
Published
2024-11-04
DOI
https://doi.org/10.1038/s41590-024-01998-4
Citations
3
Primary Topic
Coenzyme Q10 studies and effects
Type
article
Field-Weighted Citation Impact
0.70

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article

Novel coenzyme Q6 genetic variant increases susceptibility to pneumococcal disease

Michelle K. Bryant, Pallavi Chandra, Emma C. Walker, Sharon Celeste Morley et al.
3 citations
Nature Immunology
Coenzyme Q10 studies and effects
0.70
article

Novel coenzyme Q6 genetic variant increases susceptibility to pneumococcal disease

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

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.

Nature ImmunologyVol. 25(12)
The Kids Research Institute Australia (AU), The University of Western Australia (AU), Washington University in St. Louis (US), Princess Margaret Hospital for Children (AU), Queen Elizabeth II Medical Centre (AU), Center for Global Health (US), Pathwest Laboratory Medicine (AU), Perth Children's Hospital, Indiana University – Purdue University Indianapolis (US), Case Western Reserve University (US), Papua New Guinea Institute of Medical Research (PG)
Children's Discovery Institute, Alvin J. Siteman Cancer Center, Georgia Clinical and Translational Science Alliance, National Institutes of Health, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of Allergy and Infectious Diseases, National Center for Research Resources
Zero hunger
Openalex Percentile: Top 29%
Coenzyme Q10 studies and effects
0.70
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