The
urea cycle functions to incorporate
ammonia, generated by normal metabolism, into
urea.
Urea cycle disorders (UCDs) are caused by loss of function in any of the
enzymes responsible for ureagenesis, and are characterized by life-threatening episodes of acute metabolic decompensation with
hyperammonemia (HA). A prospective analysis of interim HA events in a cohort of individuals with
ornithine transcarbamylase (
OTC) deficiency, the most common UCD, revealed that intercurrent
infection was the most common precipitant of acute HA and was associated with markers of increased morbidity when compared with other precipitants. To further understand these clinical observations, we developed a model system of metabolic decompensation with HA triggered by
viral infection (PR8
influenza) using spf-ash mice, a model of
OTC deficiency. Both wild-type (WT) and spf-ash mice displayed similar
cytokine profiles and lung viral titers in response to PR8
influenza infection. During
infection, spf-ash mice displayed an increase in liver
transaminases, suggesting a hepatic sensitivity to the inflammatory response and an altered hepatic immune response. Despite having no visible pathological changes by histology, WT and spf-ash mice had reduced CPS1 and OTC
enzyme activities, and, unlike WT, spf-ash mice failed to increase ureagenesis. Depression of
urea cycle function was seen in liver
amino acid analysis, with reductions seen in
aspartate,
ornithine and
arginine during
infection. In conclusion, we developed a model system of acute metabolic decompensation due to
infection in a mouse model of a UCD. In addition, we have identified metabolic perturbations during
infection in the spf-ash mice, including a reduction of
urea cycle intermediates. This model of acute metabolic decompensation with HA due to
infection in UCD serves as a platform for exploring biochemical perturbations and the efficacy of treatments, and could be adapted to explore acute decompensation in other types of
inborn errors of metabolism.