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

A number of animal models have been developed for studying the pathogenesis and evaluating countermeasures for ZIKV infection. Rhesus macaques with subcutaneous ZIKV inoculation develop mild clinical signs that resemble the self-limiting illness in most infected immunocompetent adults (Dudley et al., 2016) . This non-human primate model provides a robust platform for the evaluation of vaccines and host immune response (Abbink et al., 2016) . However, the mild clinical disease in these primates is suboptimal for antiviral treatment evaluation. Moreover, expertise and facilities for working with non-human primates are not available in most research laboratories. Wild-type adult BALB/c mice are not susceptible to intraperitoneal ZIKV inoculation (Dick, 1952) . Suckling and young mice with intracerebral ZIKV inoculation develop disease that is localized to the central nervous system (Dick, 1952; Way et al., 1976; Weinbren and Williams, 1958; Bell et al., 1971) . Pregnant mice and fetal mice with partially intact type I interferon signaling response (fetuses of female mice deficienct in type I interferon signaling response crossed to wild-type male mice) were used to study pathogenesis in pregnancy and maternalfetal transmission, but these models are technically more demanding (Miner et al., 2016; Cugola et al., 2016) . Type I/II interferon-signaling-/ receptor-deficient mice with intraperitoneal or subcutaneous ZIKV inoculation develop fatal, disseminated infection (Lazear et al., 2016; Dowall et al., 2016; Aliota et al., 2016; Rossi et al., 2016) . These models are useful for the evaluation of countermeasures for ZIKV infection as the protective effects of antivirals drugs and vaccines are more easily observed in treated mice. However, such models have complete/nearcomplete deficiency in interferon response and do not resemble the real clinical situation in immunosuppressed humans. Moreover, these mice are suboptimal for the study of host immune response and may be too expensive for laboratories in resource-limited areas.