Lassa fever in African green monkeys: Clinical disease and fatal outcome are associated with systemic viral dissemination and inflammation

Lassa virus (LASV) causes significant human morbidity and mortality in endemic areas of West Africa. Previous studies have shown that cynomolgus macaques of non-Mauritius Asian origin best reproduce clinical features of human Lassa fever (LF). Because of the shortage of macaques caused by the COVID-19 pandemic, research on high-consequence pathogens including LASV has been severely hindered. We assessed the pathogenic potential of LASV in Mauritius-origin cynomolgus macaques (MCMs) and African green monkeys (AGMs) to find a more available alternative species to model LF. Importantly, we show similarity in transcriptomic host responses related to interferon signaling, cytokinemia, and immune cell dysregulation; however, AGMs more consistently reproduced hallmark features of LF, developing hemorrhagic manifestations closer to those seen in humans. We further show that the lethal dose 50 (LD₅₀) of LASV in mucosally exposed AGMs is approximately 27 plaque-forming units (PFU). This low LD₅₀ highlights the concern about the public health threat posed by LASV.