Our mouse model is also useful for

Our mouse model is also useful for studying ZIKV\'s tissue tropism and potential complications of severe ZIKV infection. In addition to the reported findings of detectable virus particles and/or RNA in the brain, spinal cord, kidney, spleen, liver, testis, ovary, heart, lung, muscle, and blood of types I/II interferon-signaling-/receptor-deficient mice with ZIKV infection, our study identified intestine, pancreas, and salivary gland as other possible tissues and anatomical sites for virus infection (Dick, 1952; Lazear et al., 2016; Dowall et al., 2016; Aliota et al., 2016; Rossi et al., 2016). This tissue tropism of ZIKV in our mouse model concurs with the in-vitro observation that ZIKV efficiently replicates in diverse cell types of neuronal, testicular, prostatic, renal, intestinal, hepatic, and placental origin (Chan et al., 2016b; Brault et al., 2016; Hughes et al., 2016). Such degree of virus dissemination and multi-organ involvement is also compatible with the clinical findings in patients with severe and/or fatal ZIKV infection, in whom viral particles and/or RNA were detected in multiple organs at post-mortem examination (Pan American Health Organization/World Health Oganization (PAHO/WHO), 2015; Sarmiento-Ospina et al., 2016; Arzuza-Ortega et al., 2016). While inflammatory neurological complications, such as Guillain-Barré syndrome, meningoencephalitis, and myelitis, have been recently reported in patients with ZIKV infection, inflammatory disorders of the other non-neuronal tissues were not well recognized (Cao-Lormeau et al., 2016; Carteaux et al., 2016; Mecharles et al., 2016). Our findings showed that aniracetam could be observed in multiple organs including the testis, kidney, spleen, liver, intestine, pancreas, lung, and salivary gland outside the nervous system. 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 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 (Govero et al., 2016). 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.