The ongoing Zika virus (ZIKV) epidemic and unexpected clinical outcomes, including
Guillain-Barré syndrome and birth defects, has brought an urgent need for animal models.
We evaluated infection and pathogenesis with contemporary and historical ZIKV strains
in immunocompetent mice and mice lacking components of the antiviral response. Four-
to six-week-old Irf3(-/-)Irf5(-/-)Irf7(-/-) triple knockout mice, which produce little
interferon α/β, and mice lacking the interferon receptor (Ifnar1(-/-)) developed neurological
disease and succumbed to ZIKV infection, whereas single Irf3(-/-), Irf5(-/-), and
Mavs(-/-) knockout mice exhibited no overt illness. Ifnar1(-/-) mice sustained high
viral loads in the brain and spinal cord, consistent with evidence that ZIKV causes
neurodevelopmental defects in human fetuses. The testes of Ifnar1(-/-) mice had the
highest viral loads, which is relevant to sexual transmission of ZIKV. This model
of ZIKV pathogenesis will be valuable for evaluating vaccines and therapeutics as
well as understanding disease pathogenesis.