Zika Virus Infection in Dexamethasone-immunosuppressed Mice Demonstrating Disseminated Infection with Multi-organ Involvement Including Orchitis Effectively Treated by Recombinant Type I Interferons

Chan, Jasper Fuk-Woo; Zhang, Anna Jinxia; Chan, Chris Chung-Sing; Yip, Cyril Chik-Yan; Mak, Winger Wing-Nga; Zhu, Houshun; Poon, Vincent Kwok-Man; Tee, Kah-Meng; Zhu, Zheng; Cai, Jian-Piao; Tsang, Jessica Oi-Ling; Chik, Kenn Ka-Heng; Yin, Feifei; Chan, Kwok-Hung; Kok, Kin-Hang; Jin, Dong-Yan; Au-Yeung, Rex Kwok-Him; Yuen, Kwok-Yung

Finally, our mouse model also provided a novel avenue for the evaluation of anti-ZIKV treatment. Type I interferons have broad-spectrum antiviral activities including those against ZIKV, but type I interferonsignaling-/receptor-deficient mice were not suitable for evaluation of the effects of recombinant type I interferons. We therefore evaluated the antiviral effects of two commercially available preparations of recombinant type I interferons in this new mouse model (Hamel et al., 2015; Zumla et al., 2016; Chan et al., 2013; Chan et al., 2015b) . We showed that the early use of either drug was associated with improved clinical outcome with no fatality (100% fatality in untreated mice), markedly decreased inflammatory response after dexamethasone withdrawal, and reduced viral loads in various tissues of the mice as compared to those of the untreated mice. The viral load reductions were especially significant in the early phase of the disease (5 dpi), when the mice were on dexamethasone. These findings suggested that the early use of recombinant interferons might help to control viral replication during the initial phase of infection, and prevent the subsequent development of severe complications related to an exaggerated immune response in the presence of high viral loads as seen in the untreated mice. It is important to further confirm these results in our mouse model using different ZIKV strains and in clinical trials because ZIKV antagonizes mouse STAT2 less efficiently than human STAT2, and thus may be more susceptible to type I interferons in mice (Grant et al., 2016) . While most patients with mild ZIKV infection may not require systemic interferon treatment, clinical trials should be considered to evaluate the benefits of the early use of interferon treatment in patients at risk of developing severe ZIKV-associated complications, such as those with underlying comorbidities (Sarmiento-Ospina et al., 2016) . The increased risk of fetal loss and low birth weight associated with interferon therapy in the first trimester of pregnancy may be outweighed by the risk of congenital malformations due to ZIKV infection. The optimal timing of treatment commencement should be further investigated as late commencement of interferon treatment may be useless or deleterious and should be avoided (Solomon et al., 2003) .