Infection by Zika viruses requires the transmembrane protein AXL, endocytosis and low pH

Abstract

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.

Does the human placenta express the canonical cell entry mediators for SARS-CoV-2?

“…S2). Next, we investigated the expression of the AXL receptor for ZIKV [85,86] as well as other related molecules such as CD209 [87] and TYRO3 [88]. Consistent with vertical transmission, AXL, the preferred receptor for ZIKV, was highly expressed by the cells of the human placenta and chorioamniotic membranes throughout gestation (Fig.…”

Inhibition of the replication of SARS-CoV-2 in human cells by the FDA-approved drug chlorpromazine

“…This first antipsychotic medication was discovered in 1952 by Jean Delay and Pierre Deniker at Sainte Anne hospital (2). In addition to its antipsychotic activity, a growing body of in vitro studies has demonstrated antiviral properties, for example against influenza (3), hepatitis viruses (4), alphaviruses (5), JC virus (6), Japanese encephalitis virus (7), bronchitis-virus (8), MHV-2 (9), Zika virus (10) or dengue virus (11). CPZ has also been shown to have antiviral activity against coronaviruses in multiple studies (12)(13)(14).…”

Bafilomycin A1 and U18666A Efficiently Impair ZIKV Infection

“…Bafilomycin A1 is a well-characterized inhibitor of the V-ATPase and it has been frequently used to restrain the infection of viruses internalized by receptor-mediated endocytosis. Persaud et al [30] demonstrate that this compound inhibits the entry of ZIKV MR766 strain in Vero and Cf2Th cells. Our data show that bafilomycin A1 strongly impairs the entry of ZIKV Uganda 976 (known to cause only mild symptoms) and ZIKV French Polynesia PF13/251013-18 (associated with neurological complications) in A549 and in SH-SY5Y cells.…”

“…Persaud et al [30] showed that the acidification of the endosomal compartment is crucial for the entry of the ZIKV-MR766 strain. We wondered whether this would differ between a strain responsible for only causing mild symptoms (Uganda 976) and a strain known to be associated with neurological complications (PF13/251013-18).…”