Effects of dietary iron restriction on Junín virus disease in a humanized transferrin receptor 1 mouse model

Five New World mammarenaviruses (NWM) cause severe hemorrhagic fever and threaten human health in South American communities where they are endemic. No FDA-approved antiviral drugs exist to treat these viral infections, and treatment options are urgently needed. Laboratory mice genetically modified to express human transferrin receptor 1 (huTfR1 Tg mice) are susceptible to Junín virus (JUNV), which, like other pathogenic NWMs, enters cells by attaching to the receptor’s apical domain. However, these mice exhibit physiological abnormalities, thereby limiting the model’s utility. In contrast, transgenic mice that express a murine TfR1 with a human apical domain (huApTfR1 Tg mice) are physiologically normal but more refractory to JUNV disease. Here, we investigated whether dietary iron restriction increases huApTfR1 expression, thereby promoting greater JUNV entry and more severe disease in response to reduced iron bioavailability. While a significant increase in huApTfR1 expression in target tissues was observed in mice raised on a low-iron diet, it did not confer greater susceptibility to severe JUNV disease. Notably, the low-iron diet resulted in iron-deficiency anemia and significantly lower body weight in the mice. Although our findings indicate that dietary iron restriction upregulates huApTfR1 expression and induces iron-deficiency anemia, it does not enhance mortality following JUNV challenge.