siRNA screen for genes that affect Junín virus entry uncovers voltage-gated calcium channels as a therapeutic target.
New World hemorrhagic fever arenavirus infection results in 15 to 30% mortality in humans. We performed a high-throughput small interfering RNA screen with Junín virus glycoprotein-pseudotyped viruses to find potential host therapeutic targets. Voltage-gated calcium channel (VGCC) subunits, for which there are Food and Drug Administration (FDA)-approved drugs, were identified in the screen. Knockdown of VGCC subunits or treatment with channel blockers diminished Junín virus-cell fusion and entry into cells and thereby decreased infection. Gabapentin, an FDA-approved drug used to treat neuropathic pain that targets the α₂δ₂ subunit, inhibited infection of mice by the Candid 1 vaccine strain of the virus. These findings demonstrate that VGCCs play a role in virus infection and have the potential to lead to therapeutic intervention of New World arenavirus infection.
Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Madakasira
M
Lavanya
Christian D
CD
Cuevas
Monica
M
Thomas
Sara
S
Cherry
Susan R
SR
Ross
D000588:Amines / Q000494:pharmacology; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000235:genetics* / Q000378:metabolism*; D002459:Cell Fusion; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002522:Chlorocebus aethiops; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology; D000077206:Gabapentin; D055785:Gene Knockdown Techniques; D057166:High-Throughput Screening Assays; D054884:Host-Pathogen Interactions / Q000235:genetics; D006801:Humans; D018051:Junin virus / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D058990:Molecular Targeted Therapy; D011485:Protein Binding / Q000187:drug effects; D021122:Protein Subunits / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics*; D011990:Receptors, Transferrin / Q000378:metabolism; D014709:Vero Cells; D053586:Virus Internalization / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D000588:Amines; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D003509:Cyclohexanecarboxylic Acids; D021122:Protein Subunits; D034741:RNA, Small Interfering; D011990:Receptors, Transferrin; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin