Acute metabolic decompensation due to influenza in a mouse model of ornithine transcarbamylase deficiency

Abstract

Summary The urea cycle functions to incorporate ammonia, generated by normal metabolism, into urea. Urea cycle disorders (UCD) 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 patients 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 to 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 WT and spf-ash displayed similar cytokine profiles and lung viral titers in response to PR8 influenza infection. During infection, spf-ash displayed an increase in liver transaminases suggesting a hepatic sensitivity to the inflammatory response and an altered hepatic immune response. Despite having no visible pathologic changes by histology, WT and spf-ash had reduced CPS1 and OTC enzyme activities, and unlike WT, spf-ash 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 urea cycle disorder. 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 may be adapted to explore acute decompensation in other types of inborn errors of metabolism.