# HUMAN VARIANT IN CoQ BIOSYNTHESIS IMPAIRS LUNG IMMUNITY IN ACUTE PNEUMONIA

> **NIH NIH R21** · WASHINGTON UNIVERSITY · 2020 · $196,459

## Abstract

PROJECT SUMMARY
 Pneumococcal pneumonia is a major killer of children worldwide. Acute lower respiratory infection (ALRI)
causes up to 15% of early childhood deaths annually. Some pediatric populations, such as children in Papua
New Guinea (PNG), suffer more severe ALRI than others. Most ALRI in PNG children is pneumococcal in origin.
While increased ALRI severity may be attributed to environmental factors, we hypothesized that some
populations could harbor genetic variants that increase susceptibility. By sequencing pediatric cases of
pneumococcal ALRI and control samples, we identified a single nucleotide variant (SNV) in the gene COQ6 that
may underlie severe pneumococcal ALRI susceptibility.
 COQ6 encodes coenzyme q6, which is required to synthesize CoQ, a membrane lipid enriched in
mitochondria that has a critical function in cellular ATP generation. Reduced CoQ has been reported in critically
ill patients, and CoQ-associated metabolic defects may underlie diverse disease states, such as metabolic
syndrome and Parkinson's disease. COQ6, like all enzymes in the CoQ biosynthetic pathway, is highly
conserved from yeast to mammals. Thus, the SNV, which converts a conserved aspartate to a tyrosine (DY)
residue, occurs in a biosynthetic pathway essential to mitochondrial bioenergetics, disruption of which results in
multiple pathophysiological conditions.
 We generated two model systems to show that the DY coding change (termed COQ6DY) results in
dysfunctional COQ6. First, yeast expressing only the human COQ6DY cannot use glycerol as a carbon source,
while control yeast expressing the wild-type human COQ6 can, indicating that COQ6DY impairs CoQ production
and thus mitochondrial ATP production. Second, we generated a new mouse model, using CRISPR to introduce
the analogous DY SNV into the conserved endogenous murine Coq6 locus. Animals have been back-crossed,
and homozygous Coq6DY mice from two founder lines exhibited increased mortality and increased bacterial
dissemination following lung infection with pneumococcus. We therefore have strong preliminary data suggesting
that the COQ6DY SNV contributes to increased severity of pneumococcal ALRI in children. In Aim 1, we will use
our established yeast model to elucidate how COQ6DY disrupts CoQ biosynthesis. In Aim 2, we will i) use our
established mouse model to define the pathophysiological effects of Coq6DY on the host immune response and
on lung tissue, ii) test whether Coq6DY impacts the function of hematopoietic cells, non-hematopoietic cells, or
both, and iii) test if exogenous therapy with CoQ can rescue mice expressing Coq6DY during pneumococcal
infection. Completion of this proposal will support a future R01 application probing the molecular mechanism by
which COQ6DY disrupts CoQ biosynthesis and therefore mitochondrial metabolism – providing fundamental
knowledge applicable to diverse diseases. This study will also lay the groundwork essential to developing new
adjunctive thera...

## Key facts

- **NIH application ID:** 9819772
- **Project number:** 5R21AI142723-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Sharon Celeste Morley
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $196,459
- **Award type:** 5
- **Project period:** 2018-11-06 → 2021-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9819772

## Citation

> US National Institutes of Health, RePORTER application 9819772, HUMAN VARIANT IN CoQ BIOSYNTHESIS IMPAIRS LUNG IMMUNITY IN ACUTE PNEUMONIA (5R21AI142723-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9819772. Licensed CC0.

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