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

To investigate the possible effects of immune reconstitution in the dexamethasone-immunosuppressed mice, dexamethasone was stopped after 9 dpi. This led to prominent weight loss and increased symptoms in the dexamethasone-immunosuppressed mice (groups 1 and 2). The most prominent body weight loss was observed in the male mice with dexamethasone immunosuppression and ZIKV inoculation (group 1), with all 6 mice having weight loss of ≥ 10% at 12 dpi (Fig. 1A) . All of the female mice with dexamethasone immunosuppression and ZIKV inoculation (group 2) also had progressive weight loss and 4/6 (66.7%) of them had ≥ 10% weight loss at 14 dpi. In contrast, none of the mice with dexamethasone immunosuppression from 3 days before to 13 days post-infection (group 9) developed abrupt weight loss between 10 dpi and 14 dpi (Fig. 1A) . The weight loss of mice in groups 1 and 2 became consistently more than those of their comparators in the other control groups (groups 3 to 8), including those in the dexamethasone-immunosuppressed mice with mock infection (groups 5 and 6) since 10 dpi (P b 0.05). Together, these findings suggested that the combination of immune reconstitution after dexamethasone withdrawal and disseminated virus infection were responsible for the abrupt clinical deterioration. All of the mice in groups 1 and 2 developed rapid breathing, lethargy, and/or ruffled fur since 11 dpi (group 1) or 12 dpi (group 2), shortly after dexamethasone was stopped (Fig. 1B) . The reasons for the earlier onset of weight loss and symptoms in the male mice were not fully understood, but might be related to the higher cumulative dose of dexamethasone because of their higher baseline body weights and/or possible effects of androgen on virus replication (Tian et al., 2012) . Based on the predefined criteria, all 6 (100%) male and 4/6 (66.7%) female mice were euthanized at 12 dpi and 14 dpi, respectively (Fig. 1C) . Comparatively, all the mice in the other control groups (groups 3 to 9) had either gained weight or had b 5% weight loss with spontaneous recovery at 14 dpi (Fig. 1A) , remained asymptomatic (Fig. 1B) , and survived through the study period (Fig. 1C) .