A transgenic Syrian hamster model for New World hemorrhagic fever mammarenavirus infection

Mammarenaviruses are endemic in rodent populations worldwide, and their zoonotic transmission can lead to a severe, life-threatening hemorrhagic fever (HF) syndrome. In the Americas, five New World mammarenaviruses (NWMs) are known to cause HF. As vaccines and antiviral therapy options are limited, these viruses pose a significant public health risk and a threat to national security. Research into NWM pathogenesis and the development of effective countermeasures is restricted by the shortage of small-animal models that faithfully reproduce human disease. The pathogenic NWMs use human transferrin receptor 1 (hTfR1) as the receptor for cellular entry. Here, we describe the development of an hTfR1 knock-in golden Syrian hamster line and its susceptibility to Junín virus (JUNV) infection. This transgenic hamster infection model supports TfR1-mediated entry as an essential step in JUNV pathogenesis and provides a novel small-animal model to advance the development of promising host receptor-directed therapies and direct-acting antivirals to improve outcomes in patients with severe disease caused by pathogenic NWMs.