A novel function for the CoQ10 biosynthetic complex in anti-pneumococcal macrophage function

Abstract

Despite the recent introduction of pneumococcal polysaccharide and conjugate vaccines, Streptococcus pneumoniae infection remains a leading cause of illness and death worldwide. In particular, infants in Papua New Guinea are at increased risk of severe pneumococcal pneumonia compared to infants in similar countries. We sought to determine if a novel genetic variant could explain this increased susceptibility. Whole exome sequencing revealed a single nucleotide variant (D308Y) in the gene encoding COQ6 (COQ6DY), a monooxygenase required for CoQ10 biosynthesis. We have utilized both a Saccharomyces cerevisiae model and a mouse model of COQ6DY to show that despite adequate production of CoQ10, this variant directly causes increased susceptibility to S. pneumoniae. This variant represents a previously unknown function of the CoQ10 biosynthetic complex that does not exert its effects through CoQ10 deficiency but rather through alterations of mitochondrial function and metabolism. These mitochondrial deficits in COQ6DY macrophages are sufficient to abrogate macrophage killing of S. pneumoniae and alter the coordination of the downstream immune response. In conclusion, we have identified a novel susceptibility allele to S. pneumoniae infection that exerts its effects via alterations in macrophage mitochondrial function. Supported by NIH (R21 AI142723), SLCH Children's Discovery Institute (PD-II-2018-742)