Bibliographic Details
| Title: |
Novel coenzyme Q6 genetic variant increases susceptibility to pneumococcal disease |
| Authors: |
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 |
| Source: |
Nature Immunology; 20240101, Issue: Preprints p1-12, 12p |
| 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. COQ6encodes 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 Coq6exhibited increased mortality after pneumococcal lung infection, confirming causality. Bone marrow chimeric mice further revealed that expression of variant Coq6in recipient (that is, nonhematopoietic) tissues conferred increased mortality. Variant Coq6maintained ubiquinone biosynthesis, while accelerating metabolic remodeling after pneumococcal challenge. Identification of this COQ6variant 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. |
| Database: |
Supplemental Index |
