Studying immunity to zoonotic diseases in the natural host — keeping it real

Key Points Zoonotic viruses pose a serious threat to human and animal health. Studying the immune response to zoonotic pathogens in the natural reservoir hosts, rather than traditional animal models, offers important insights into control strategies. Comparative studies in natural host systems have provided key information and improved our understanding of co-evolution of hosts and pathogens. This could lead to the discovery of novel immune mechanisms that control viral replication. Understanding the differences between the immune systems of domesticated and wild animal hosts and comparing them to the human immune system is crucial for unravelling the complex disease mechanisms involved in zoonotic infections and for developing new strategies for disrupting their transmission to humans. The use of non-traditional animal models for research poses many challenges. These include the need for specialist high-biosecurity containment facilities, a lack of species-specific reagents for immunology studies, and complex husbandry, ethics and welfare issues. Whole-genome sequencing and comparative analysis of host species have provided key insights into how different immune responses are made to the same pathogen. The identification of key differences in immune pathways between susceptible and non-susceptible hosts might offer clues for developing disease intervention strategies, including new antiviral vaccines and therapies, and disease-resistant animals. Immunology is traditionally viewed as a science of 'mice and men'. However, key insights can come from the study of immune responses in livestock or wild animals. The fact that the most deadly pathogens of humans are often zoonotic in nature lends further weight to the importance of this research. The authors discuss the benefits of, and challenges posed by, these studies. Zoonotic viruses that emerge from wildlife and domesticated animals pose a serious threat to human and animal health. In many instances, mouse models have improved our understanding of the human immune response to infection; however, when dealing with emerging zoonotic diseases, they may be of limited use. This is particularly the case when the model fails to reproduce the disease status that is seen in the natural reservoir, transmission species or human host. In this Review, we discuss how researchers are placing more emphasis on the study of the immune response to zoonotic infections in the natural reservoir hosts and spillover species. Such