Novel coenzyme Q6 genetic variant increases susceptibility to pneumococcal disease

Area of Science:

• Genetics
• Infectious Diseases
• Metabolism

Background:

• Acute lower respiratory tract infection (ALRI) is a leading cause of death in children globally.
• Children in Papua New Guinea (PNG) face high ALRI morbidity, particularly from Streptococcus pneumoniae.
• PNG's population exhibits significant genetic diversity, suggesting a potential role for host genetics in disease susceptibility.

Purpose of the Study:

• To investigate whether genetic variants contribute to increased ALRI morbidity in children from PNG.
• To identify specific genetic factors associated with severe ALRI in this population.

Main Methods:

• Whole-exome sequencing was performed on a pilot cohort of children with ALRI.
• A novel single-nucleotide variant (SNV) in the COQ6 gene was identified in cases.
• Association of the COQ6 SNV with ALRI was replicated in an independent cohort.
• Causality was confirmed using mouse models of pneumococcal infection and bone marrow chimeras.

Main Results:

• Homozygosity for a novel SNV in COQ6 was significantly associated with ALRI in children.
• Mice with the homologous Coq6 variant showed increased mortality after pneumococcal infection.
• Nonhematopoietic expression of variant Coq6 increased mortality, indicating a role beyond immune cells.
• Variant Coq6 altered metabolic remodeling during infection while maintaining ubiquinone biosynthesis.

Conclusions:

• A specific COQ6 genetic variant provides a basis for increased pneumonia susceptibility in PNG children.
• COQ6 plays a previously unrecognized role in regulating inflammatory-mediated metabolic remodeling during respiratory infections.
• This finding highlights the importance of host genetics in understanding ALRI pathogenesis and developing targeted interventions.