AA Amyloidosis In Island Foxes (Urocyon Littoralis): Pathology, Risk Factors, And The Genetic Basis For Disease

Abstract

The island fox (Urocyon littoralis) is an endangered species that lives exclusively on the California Channel islands. Island foxes inhabit six of the eight Channel islands and have evolved into six genetically distinct, island‐specific subspecies. Systemic amyloidosis is highly prevalent in island foxes and is a threat to species recovery. I have identified the type of amyloid, described the lesions of amyloidosis in foxes, and investigated the risk and underlying molecular mechanisms of disease. Based on immunoreactivity to anti‐canine AA antibody and protein sequencing by mass spectrometry, amyloid in foxes has been identified as amyloid A (AA). AA amyloidosis occurs following prolonged elevation of the acute phase protein serum amyloid A (SAA), secondary to chronic infectious or inflammatory disease. Amyloid aggregates in tissue were most common in kidney, spleen and the oral cavity, and amyloid in foxes had a propensity for deposition along basement membranes. Sequencing of the SAA protein identified it as a 111 amino acid long protein with multiple isoforms and an amyloid‐prone, N‐terminal segment. Risk factors for disease were identified by multivariable logistic regression as older age, the San Clemente island subspecies, captivity and nephritis. Increased risk for disease in one subspecies, in addition to the lack of reports of AA amyloidosis in gray fox, the closest genetic relative to island fox, suggest a possible genetic association with disease. Examination of gene transcript levels in the SAA transcription pathway revealed SAA, IL6, IL1α, IL1β, and C/EBP‐δ transcripts were significantly elevated in island foxes with AA amyloidosis, and higher SAA transcripts correlated with more severe disease. Serum SAA protein concentrations were similar in foxes that died with and without amyloidosis, suggesting serum protein levels are not an accurate indicator of disease status. Lastly, based on sequence variation in the region of the SAA gene family in island and gray foxes, 14 SNPs unique to all island fox subspecies have been identified. Understanding the influence of genetic as well as exogenous factors on AA amyloidosis in island foxes informs not only on the disease mechanism in this endangered species, but contributes to the overall understanding of the pathogenesis of AA amyloidosis.Support or Funding InformationThis work was supported by an Academic Senate Grant from the University of California, San Diego, the Karen C. Drayer Wildlife Health Center, School of Veterinary Medicine, University of California, Davis, and the ARCS Foundation of Northern California. P.M.G was funded by The Linda Munson Fellowship for Wildlife Pathology Research administered by the ACVP/STP Coalition for Veterinary Pathology Fellows and the Peter Kennedy Fellowship in Anatomic Pathology, School of Veterinary Medicine, University of California, Davis.