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

Among these non-neuronal tissues, the inflammatory reactions were most prominent in the testis of our model mice. Some patients with ZIKV infection reported hematospermia, pelvic pain, and dysuria with detectable viral particles and/or RNA in their semen (Chan et al., 2016a; Musso et al., 2015a; Foy et al., 2011) . Histological evidence of orchitis has not been reported due to the difficulty in obtaining the patients' testicular tissues for histological examination. Previous mouse Fig. 4 . Representative histological findings in the brain and kidney of dexamethasone-immunosuppressed BALB/c mice with ZIKV inoculation and dexamethasone-immunosuppressed mock-infected control mice. The brain and kidneys of all sacrificed mice were examined. Each organ was entirely embedded in one paraffin block, and one full-face paraffin section at the maximum diameter of each organ was examined per block. Sections of the brain (12 dpi) of a dexamethasone-immunosuppressed mouse with ZIKV inoculation showing (A) moderate degree of perivascular lymphocytic infiltrate and (B) marked lymphocytic infiltration in the cortical parenchyma (H&E, original magnification ×400). Section of the brain (12 dpi) of dexamethasone-immunosuppressed mock-infected mouse showing normal architecture in the parenchyma (C) (H&E, original magnification ×400). Sections of the kidney (12 dpi) showing (D) acute tubulitis with a large amount of inflammatory exudation in tubular lumens and (E) moderate degree of interstitial inflammation (H&E, original magnification ×400). (F) Section of the kidney (12 dpi) of a dexamethasone-immunosuppressed mock-infected mouse showing normal architecture (H&E, original magnification ×400). models for ZIKV infection utilizing types I/II interferon-signaling-/receptor-deficient mice have also showed that viral particles and RNA could be detected in the mice's testes, but histological analysis were not reported (Lazear et al., 2016) . The markedly necrotic and hemorrhagic seminiferous tubules observed in our mice are highly alarming as orchitis may have long-term effects on fertility. These changes were not accountable by dexamethasone-induced testicular toxicity, as they were morphologically different from the latter, and were not present in any of the testes of the control mice with dexamethasone treatment and mock infection (Khorsandi et al., 2013) . During revision of this work, similar findings were reported in the testes of C57BL/6 mice treated with anti-Ifna1 blocking monoclonal antibody and inoculated with ZIKV . Clinical studies to confirm the presence of orchitis and to assess the fertility of convalescent male patients should be conducted to ascertain the long-term consequences of ZIKV infection regarding reproductive and hormonal derangements. Inflammation of other organs, such as acute tubulitis, interstitial nephritis, sialadenitis, hepatitis, enteritis, and acute pancreatitis have been reported in patients with ZIKV or other flavivirus infections (Chan et al., 2016a; Sarmiento-Ospina et al., 2016; Arzuza-Ortega et al., 2016; Duijster et al., 2016; Bonaldo et al., 2016; Gourinat et al., 2015; Musso et al., 2015b; Mercado et al., 2016; Bhagat et al., 2012; Torres et al., 2000; Macnamara, 1954; Chatterjee et al., 2014) . These potential complications may be increasingly recognized as the ZIKV epidemic continues to expand into developed countries with a large ageing and immunosuppressed population.