A novel variant in CoQ biosynthesis highly prevalent in Papua New Guinea children increases mortality following bacterial pneumonia

Abstract To identify immune variants predisposing to severe pneumonia, we performed whole exome sequencing in a pediatric population highly susceptible to acute lower respiratory infections, identifying a candidate novel variant in the CoQ biosynthetic pathway. To evaluate the effect of this variant on immune function during bacterial pneumonia, we generated a mouse line using CRISPR-Cas9 that expresses the homologous variant in the enzyme COQ6. Interestingly, we found that the variant does not result in CoQ deficiency, as other known variants in biosynthetic proteins do, however intra-tracheal S. pneumoniae infection leads to increased bacteremia and mortality in mutant mice. Mechanistic studies show that mutant macrophages have reduced pneumococcal killing in vitro, showing an intrinsic defect in innate immune function conferred by the COQ6 mutation. Variant macrophages have decreased mitochondrial respiratory capacity both at baseline and following stimulation with LPS, as well as an inability to induce mitochondrial reactive oxygen species (mROS) in response to stimulation despite increased mROS at baseline. Thus, the novel variant in a CoQ biosynthetic enzyme leads to changes in macrophage mitochondrial function and an intrinsic inability to kill internalized bacteria. As alveolar macrophages are the first responders in the lung to bacterial challenge, the inability of these macrophages to mount a sufficient immune response leads to the observed increase in mortality following bacterial pneumonia. This work describes a novel susceptibility locus to severe childhood pneumonia, and also represents the first known pathogenic variant in a CoQ biosynthetic protein that does not cause pathology resulting from CoQ deficiency.