Entry receptor LDLRAD3 is required for Venezuelan equine encephalitis virus peripheral infection and neurotropism leading to pathogenesis in mice
Natasha M. Kafai,
Hana Janova,
Matthew D. Cain,
Yael Alippe,
Stefanie Muraro,
Alan Sariol,
Michelle Elam-Noll,
Robyn S. Klein,
Michael S. Diamond
Affiliations
Natasha M. Kafai
Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
Hana Janova
Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
Matthew D. Cain
Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
Yael Alippe
Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
Stefanie Muraro
Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
Alan Sariol
Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
Michelle Elam-Noll
Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
Robyn S. Klein
Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, USA
Michael S. Diamond
Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA; The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO 63110, USA; Corresponding author
Summary: Venezuelan equine encephalitis virus (VEEV) is an encephalitic alphavirus responsible for epidemics of neurological disease across the Americas. Low-density lipoprotein receptor class A domain-containing 3 (LDLRAD3) is a recently reported entry receptor for VEEV. Here, using wild-type and Ldlrad3-deficient mice, we define a critical role for LDLRAD3 in controlling steps in VEEV infection, pathogenesis, and neurotropism. Our analysis shows that LDLRAD3 is required for efficient VEEV infection and pathogenesis prior to and after central nervous system invasion. Ldlrad3-deficient mice survive intranasal and intracranial VEEV inoculation and show reduced infection of neurons in different brain regions. As LDLRAD3 is a determinant of pathogenesis and an entry receptor required for VEEV infection of neurons of the brain, receptor-targeted therapies may hold promise as countermeasures.
