Bacterial pneumonia causes up to 15% of early childhood deaths worldwide. The incidence and severity of this is even higher among children of Papua New Guinea (PNG), suggesting a heritable component to their susceptibility. Preliminary work identified a variant in the gene COQ6 that may increase the risk of PNG children to severe pneumonia. The COQ6 gene encodes Coenzyme q6, an enzyme needed to generate CoQ10, a compound that protects cells from oxidative stress. A new mice model expressing this variant were less effective at clearing bacteria from the lung, supporting a causal association between the COQ6 variant and severe disease. We will study how the COQ6 variant impairs CoQ10 production and limits host cell tolerance to oxidative stress during lung infection.
Proposed specific aims
· Confirm an association between the COQ6 variant and disease in a larger validation cohort of PNG children with pneumonia.
· Evaluate the biochemical, cellular, and physiological consequences of the COQ6 variant during pneumococcal infection in our newly generated mouse models.
Potential impact on child health
CoQ10 is readily available as an inexpensive nutritional supplement. Our findings can uncover a highly treatable way to ameliorate severe pneumonia in vulnerable pediatric populations.