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

The dexamethasone-immunosuppressed mice with ZIKV inoculation in our study developed disseminated infection with viremia and multi-organ involvement, including the brain, urogenital tract, intestine, liver, spleen, pancreas, heart, lung, and salivary gland as evident by ZIKV-NS1 protein expression on immunohistochemical staining and/or detectable viral load in these tissues. Immunohistochemistry staining of the testis confirmed the presence of inflammatory cell infiltrate (pan-leukocyte marker CD45 +) with predominantly CD8 + T lymphocytes. Clinically, the male mice developed earlier onset of disease than the female mice, with ≥10% weight loss and ≥1 clinical sign, which warranted euthanasia at 12 dpi. Their weight loss, clinical scores, and histological evidence of inflammatory reactions were most severe soon after dexamethasone withdrawal, when viral loads had already decreased by about 2-5 log 10 copies/10 6 β-actin. Overall, these findings suggested that, like the other related flaviviruses, the host immune response might have led to marked clinical deterioration in the face of disseminated ZIKV infection at the time when immune-mediated clearance of the virus began. Our findings provided an additional explanation for the pathogenesis of fatal ZIKV infection, which has been proposed to be related to uncontrolled virus dissemination in previously described mouse models utilizing types I/II interferon-signaling-/receptor-deficient mice that were unable to mount a robust host innate immune response.