Host susceptibility to Cryptococcus neoformans and C. gattii across endothermic vertebrates: a comparative analysis

Cryptococcus neoformans and C. gattii are saprophytic fungal species complexes that cause neurologic and pulmonary diseases in humans, domestic animals, and wildlife. Animal models of cryptococcosis remain key tools to study disease pathogenesis and develop therapeutics. Comparative study of infectious diseases across animal species can provide important insights into the pathogenesis, resistance, and susceptibility to this disease. In fact, comparative analysis exposes a puzzle: rodents and rabbits, the species most often used to experimentally study cryptococcosis, are also relatively resistant to natural infection. The causes for this decreased susceptibility are not clear, but resistance to cryptococcosis appears to be multifactorial. By examining specific examples within the natural host ranges of C. neoformans and C. gattii , including nasal cryptococcosis in carnivores, pulmonary infections in horses and marine mammals, natural resistance in rabbits, and mouse strain-specific susceptibility, a theme emerges suggesting that interspecies differences in anatomy, physiology, life history, immunity, and behavior are major determinants of host susceptibility and disease pathogenesis. Since each animal presents unique considerations, and none entirely recapitulates human cryptococcosis, we highlight the importance of targeted model selection based on carefully delineated research goals. To refine model selection and facilitate new model development, it is important to understand not just the experimental context of the specific model organism, but also the unique features of natural infections. Despite these insights, the literature on animal cryptococcosis is biased toward a few species and very sparse with regard to its prevalence in free-ranging wildlife, highlighting the need for more studies in this area.