Study of Host Factor Inositol Polyphosphate-5-Phosphatase F (INPP5F) Involved In Dengue Virus Replication and Establishment of Zika Virus Infectious Animal Model

  • 吳 宇軒

Student thesis: Doctoral Thesis

Abstract

Dengue virus (DENV) infection causes dengue fever (DF) dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS) leading to severe global health problem with substantial morbidity and mortality Zika virus (ZIKV) infection caused diseases ranging from acute self-limiting febrile illness to life-threatening Guillain Barre Syndrome and other neurological disorders in adults Cumulative evidence suggests an association between ZIKV infection and microcephaly in newborn infants To date there are still no FDA-approved drugs against DENV/ZIKV infection and the virus-related diseases NGS analyses of cellular mRNAs that are modulated by DENV infection revealed the criticalness of elevated inositol polyphosphate-5-phosphatase F (INPP5F) mRNA levels upon DENV replication Our results further demonstrated that INPP5F was induced by DENV infection in a time-dependent manner and overexpression of INPP5F enhanced DENV replication In contrast knockdown of INPP5F by shRNA resulted in the suppression of DENV-2 replication through induction of Akt/NF-κB-mediated antiviral interferon (IFN) responses In addition suppression of INPP5F by a recombinant adenovirus carrying INPP5F shRNA protected ICR suckling mice from life-threatened DENV-2 infection Taken together induction of antiviral IFN responses as a result of elevated INPP5F may be a potential strategy for anti-DENV development As an alternative strategy several natural products have been reported to exhibit immunoregulatory effect We therefore selected a Schisandra chinensis extract schisandrin A and an avocado fruit extract (2R 4R)-1 2 4-trihydroxyheptadec-16-yne (THHY) to examine whether these natural products could suppress DENV-2 replication Our results indicated that Schisandrin A and THHY inhibited all DENV serotypes (1–4) virus replication in a concentration- and time-dependent manner without significant cytotoxicity Furthermore schisandrin A and THHY effectively protected ICR suckling mice from DENV-2-caused severe disease symptoms and mortality in vivo We also demonstrated that STAT1/2-mediated antiviral IFN responses contributes to the action of schisandrin A to against DENV-2 replication while NF-κB-mediated antiviral IFN responses is induced by THHY to efficiently suppress replication of all DENV serotypes (1–4) To extend the biological effect of INPP5F on similar flaviviruses we test the antiviral effect of INPP5F on zika virus (ZIKV) which has the common characteristics with DENV including mosquito-borne transmission overlapped epidemic areas and similar genericity and antigenicity Interestingly suppression of INPP5F also effectively inhibited ZIKV replication To further examine the inhibitory effect of INPP5F on ZIKV replication in vivo we established a promising small animal model using ICR suckling mice for ZIKV infection The signs of illness neurological symptoms and mortality rate could be easily monitored from ICR mice that were intracerebrally or intraperitoneally injected with ZIKV Viremic dissemination was observed in the liver spleen kidney and brain Using this mice model we were also able to demonstrate that a ZIKV inhibitor Azithromycin (Az) confers protection against ZIKV-caused neurological and life-threatening diseases In conclusion our study indicated that INPP5F downregulated Akt/NF-B-mediated antiviral IFN responses to facilitate DENV replication Natural products such as schisandrin A and THHY that enhance IFN responses are beneficial to suppress DENV infecton Additionally we established a promising ZIKV-infected small animal model which can be conveniently used for screening drugs against ZIKV and investigating the underlying mechanism of ZIKV infection and pathogenesis
Date of Award2019
Original languageEnglish
SupervisorKung-Chia Young (Supervisor)

Cite this

Study of Host Factor Inositol Polyphosphate-5-Phosphatase F (INPP5F) Involved In Dengue Virus Replication and Establishment of Zika Virus Infectious Animal Model
宇軒, 吳. (Author). 2019

Student thesis: Doctoral Thesis