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317 - A NOVEL VARIANT IN COQ10 BIOSYNTHESIS HIGHLY PREVALENT IN PAPUA NEW GUINEA CHILDREN INCREASES MORTALITY TO BACTERIAL PNEUMONIA (ID 809)

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Abstract

Background

Whole exome sequencing of Papua New Guinea (PNG) children with acute lower respiratory infection identified a highly enriched novel single nucleotide variant (SNV) in a CoQ10 biosynthetic protein. We aim to determine how this variant impairs anti-pneumococcal immune function.

Methods

We use a Crispr-CAS9 generated mouse model of the SNV to interrogate the effects of the SNV on the immune system and its response to S. pneumoniae infection. We also utilize a S. cerevisiae model of the SNV to further examine biochemical effects of the mutation.

Results

Homozygosity of the novel SNV leads to increased bacterial burden in the lungs and increased mortality during the first week of infection with S. pneumoniae. This is accompanied by increased levels of proinflammatory cytokines and marked changes in lung histology. Surprisingly, this SNV in a CoQ10 biosynthetic protein does not lead to CoQ10 deficiency but rather exerts its effect through a previously unknown second function. Mechanistic studies have revealed changes in macrophage function leading to an inability of macrophages to kill internalized pneumococci.

Conclusions

Whole exome sequencing of a population highly susceptible to pneumococcal pneumonia has revealed a novel single nucleotide variant which confers decreased anti-pneumococcal macrophage function and increased mortality to pneumococcal infection in a mouse model.

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