25-Hydroxycholesterol Protects Host Against Zika Virus Infection and Its Associated Microcephaly in a Mouse Model

Immunity. 2017 Mar 21;46(3):446-456. doi: 10.1016/j.immuni.2017.02.012. Epub 2017 Mar 14.

Abstract

Zika virus (ZIKV) has become a public health threat due to its global transmission and link to severe congenital disorders. The host immune responses to ZIKV infection have not been fully elucidated, and effective therapeutics are not currently available. Herein, we demonstrated that cholesterol-25-hydroxylase (CH25H) was induced in response to ZIKV infection and that its enzymatic product, 25-hydroxycholesterol (25HC), was a critical mediator of host protection against ZIKV. Synthetic 25HC addition inhibited ZIKV infection in vitro by blocking viral entry, and treatment with 25HC reduced viremia and conferred protection against ZIKV in mice and rhesus macaques. 25HC suppressed ZIKV infection and reduced tissue damage in human cortical organoids and the embryonic brain of the ZIKV-induced mouse microcephaly model. Our findings highlight the protective role of CH25H during ZIKV infection and the potential use of 25HC as a natural antiviral agent to combat ZIKV infection and prevent ZIKV-associated outcomes, such as microcephaly.

Keywords: 25HC; CH25H; ZIKV; antiviral immunity; microcephaly.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antiviral Agents / pharmacology*
  • Brain / drug effects
  • Disease Models, Animal
  • Fluorescent Antibody Technique
  • Humans
  • Hydroxycholesterols / pharmacology*
  • Macaca mulatta
  • Mice
  • Microcephaly / virology*
  • Microscopy, Confocal
  • Virus Internalization / drug effects
  • Zika Virus / drug effects
  • Zika Virus / physiology
  • Zika Virus Infection / complications*

Substances

  • Antiviral Agents
  • Hydroxycholesterols
  • 25-hydroxycholesterol