Extracellular acidosis enhances Zika virus infection both in human cells and ex-vivo tissue cultures from female reproductive tract

Abstract

Zika virus (ZIKV) is a flavivirus transmitted by mosquitoes of the genus Aedes, but unlike other flaviviruses, ZIKV can be sexually transmitted by vaginal intercourse. The healthy vaginal pH ranges from 4.0 to 6.0, reaching values of 6.0 to 7.0 after semen deposition. Here, we report that low extracellular pH values (range 6.2 to 6.6) dramatically increase ZIKV infection on cell lines of different origin including some derived from the female genital tract and monocyte derived macrophages. Furthermore, low pH significantly increased ZIKV infection of human ectocervix and endocervix cultured ex-vivo. Enhancement of infection by low pH was also observed using different ZIKV strains and distinct methods to evaluate viral infection, i.e., plaque assays, RT-PCR, flow cytometry and fluorescence microscopy. Analysis of the mechanisms involved revealed that the enhancement of ZIKV infection induced by low pH was associated with an increased binding of the viral particles to the heparan sulfate expressed on the target cell surface. Acidosis represents a critical but generally overlooked feature of the female genital tract, with major implications for sexual transmission diseases. Our results suggest that low vaginal pH might promote male-tofemale transmission of ZIKV infection.

Antiviral Activities of Heparan Sulfate Mimetic RAFT Polymers Against Mosquito-borne Viruses

“…40 Several studies support the dependence of ZIKV cell entry on HS. 41,42 Other research, however, claims that HS is not essential for ZIKV attachment to cells, 43 or even that heparin promotes ZIKV infection in Vero cells. 44 In accordance with other studies on poly(SS) of various MW, 19,33,36 the HS mimetic polymer poly(SS) of M n 25.5 kDa, showed potent inhibition of ZIKV infection in different cell models, which provides us with an important tool to clarify the interaction of HS and ZIKV by identifying the core structure essential for ZIKV cell attachment.…”

Acidic Microenvironments Found in Cutaneous Leishmania Lesions Curtail NO-Dependent Antiparasitic Macrophage Activity

“…Although many antimicrobial peptides require low pH for their optimal activity [reviewed in: ( 61 )], to the best of our knowledge, data on the impact of low pH on antimicrobial macrophage activity is limited. Extracellular acidosis reportedly enhances Zika virus replication in various cells including human monocytes ( 62 ). Enhanced viral replication in this study was linked to increased viral attachment to heparan sulphate, which is expressed on the surface of host cells ( 62 ).…”

“…Extracellular acidosis reportedly enhances Zika virus replication in various cells including human monocytes ( 62 ). Enhanced viral replication in this study was linked to increased viral attachment to heparan sulphate, which is expressed on the surface of host cells ( 62 ). In a porcine model of cystic fibrosis, airway surface liquid was more acidic compared to healthy lungs ( 63 ).…”