Going wild: prioritizing experimental models of rodent-borne viruses to decode zoonotic spillover and pandemic risk

Rodent-borne viruses pose threats to global health because of their capacity for zoonoses with the potential to cause outbreaks of high morbidity and mortality. Gaining a deeper understanding of how these viruses persist in their reservoir hosts and spillover into human populations requires an integrated approach blending both laboratory- and field-based research. Here, we review our current understanding of rodent-borne virus dynamics-primarily mammarenaviruses and orthohantaviruses-within their natural rodent reservoirs. We highlight key insights gained from experimental infection models seeking to replicate authentic host-pathogen interactions under controlled conditions. We argue that expanding and refining experimental models, particularly those that simulate natural reservoir conditions, is crucial to identifying the host and viral factors facilitating viral persistence in nature, and transmission to human populations. We propose a framework for future research that prioritizes hypothesis-driven research in model systems that are both natural and translatable to bridge these knowledge gaps.