Zika virus (ZIKV) is a flavivirus that has recently emerged from Uganda, into Asia, across the Pacific and now into the Americas. ZIKV infection is transmitted to humans by the bite of an infected mosquito. Person to person sexual transmission of ZIKV has also been documented. ZIKV infection poses a major threat to unborn children because it efficiently crosses the placental barrier to mediate maternal to fetal transmission in utero. Fetal infection can lead to varied pathologies including microcephaly and fetal death. Little is known of how placental cells respond to infection to control ZIKV tropism and to mount innate immune defenses to protect against ZIKV spread and fetal infection. Our preliminary studies show that ZIKV triggers placental innate immune activation through RIG-I sensing of viral pathogen associated molecular patterns (PAMPS) but that it directs a broad blockade to cytokine signaling through signal transducer and activator of transcription (STAT) proteins in the infected cell. This broad STAT suppression attenuates interferon (IFN) innate immune defenses to support virus replication and spread to the fetus. This proposal will investigate the central hypotheses that the outcome of ZIKV infection and disease is linked with regulation of innate immune defenses and control of JAK-STAT signaling, and that viral evasion of host defenses enables maternal-fetal ZIKV transmission and fetal disease. We will conduct three Aims: 1) Determine the molecular mechanisms by which ZIKV induces innate immune responses in key cell types of the maternal-fetal interface throughout human pregnancy; 2) Determine the molecular mechanisms of broad JAK-STAT regulation by ZIKV, and 3) Define the role of innate immune activation and STAT regulation of antiviral defenses to control ZIKV infection of human placental cells ex vivo, and determine how viral innate immune evasion impacts fetal disease in the STAT2-KI model of maternal/fetal transmission.

Public Health Relevance

Zika virus is an emerging public health threat to pregnant women all over the world wherein infection is transferred from mother to fetus to cause fetal disease. Our studies are designed to reveal the virus and host processes that trigger and control antiviral immunity against Zika virus in the placenta.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI145296-01
Application #
9764818
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Woodson, Sara Elaine
Project Start
2019-03-01
Project End
2024-02-29
Budget Start
2019-03-01
Budget End
2020-02-29
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Washington
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195