TY - JOUR
T1 - Infection by Zika viruses requires the transmembrane protein AXL, endocytosis and low pH
AU - Persaud, Mirjana
AU - Martinez-Lopez, Alicia
AU - Buffone, Cindy
AU - Porcelli, Steven A.
AU - Diaz-Griffero, Felipe
N1 - Publisher Copyright:
© 2018 Elsevier Inc.
PY - 2018/5
Y1 - 2018/5
N2 - The recent Zika virus (ZIKV) outbreak in Brazil has suggested associations of this virus infection with neurological disorders, including microcephaly in newborn infants and Guillian-Barré syndrome in adults. Previous reports have shown that AXL, a transmembrane receptor tyrosine kinase protein, is essential for ZIKV infection of mammalian cells, but this remains controversial. Here, we have assessed the involvement of AXL in the ability of ZIKV to infect mammalian cells, and also the requirement for endocytosis and acidic pH. We demonstrated that AXL is essential for ZIKV infection of human fibroblast cell line HT1080 as the targeted deletion of the gene for AXL in HT1080 cells made them no longer susceptible to ZIKV infection. Our results also showed that infection was prevented by lysosomotropic agents such as ammonium chloride, chloroquine and bafilomycin A1, which neutralize the normally acidic pH of endosomal compartments. Infection by ZIKV was also blocked by chlorpromazine, indicating a requirement for clathrin-mediated endocytosis. Taken together, our findings suggest that AXL most likely serves as an attachment factor for ZIKV on the cell surface, and that productive infection requires endocytosis and delivery of the virus to acidified intracellular compartments.
AB - The recent Zika virus (ZIKV) outbreak in Brazil has suggested associations of this virus infection with neurological disorders, including microcephaly in newborn infants and Guillian-Barré syndrome in adults. Previous reports have shown that AXL, a transmembrane receptor tyrosine kinase protein, is essential for ZIKV infection of mammalian cells, but this remains controversial. Here, we have assessed the involvement of AXL in the ability of ZIKV to infect mammalian cells, and also the requirement for endocytosis and acidic pH. We demonstrated that AXL is essential for ZIKV infection of human fibroblast cell line HT1080 as the targeted deletion of the gene for AXL in HT1080 cells made them no longer susceptible to ZIKV infection. Our results also showed that infection was prevented by lysosomotropic agents such as ammonium chloride, chloroquine and bafilomycin A1, which neutralize the normally acidic pH of endosomal compartments. Infection by ZIKV was also blocked by chlorpromazine, indicating a requirement for clathrin-mediated endocytosis. Taken together, our findings suggest that AXL most likely serves as an attachment factor for ZIKV on the cell surface, and that productive infection requires endocytosis and delivery of the virus to acidified intracellular compartments.
KW - Clathrin
KW - Endocytosis
KW - Entry
KW - Low-pH
KW - ZIKA
UR - http://www.scopus.com/inward/record.url?scp=85044165767&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85044165767&partnerID=8YFLogxK
U2 - 10.1016/j.virol.2018.03.009
DO - 10.1016/j.virol.2018.03.009
M3 - Article
C2 - 29574335
AN - SCOPUS:85044165767
SN - 0042-6822
VL - 518
SP - 301
EP - 312
JO - Virology
JF - Virology
ER -