Adulthood Sequelae of Congenital Zika Virus Infection in Mice.

Zika virus (ZIKV) is a mosquito-borne flavivirus that was originally identified in 1947 from a sentinel Rhesus monkey in the Zika forest in Uganda (Dick et al., 1952). Prior to 2007, ZIKV infections occurred periodically in Africa and Asia with mild, self-limiting febrile illnesses such as rash, headache, conjunctivitis, myalgia, and arthralgia. However, in the past decade, ZIKV became explosive in causing outbreaks and epidemics, first on Yap Island in the Federated States of Micronesia in 2007, second in French Polynesia in 2013, third in northeastern Brazil in late 2014, followed by a rapid spread to other countries in the Americas in 2015–2016, including autochthonous transmissions in Florida and Texas in the United States (Frieden et al., 2016). During the recent outbreaks and epidemics in Asian and the Americas, ZIKV infection has caused devastating severe diseases, particularly Guillain-Barre syndrome in adults and congenital malformations in fetus, among which congenital malformation is unique to ZIKV infection when compared with diseases caused by other flavivirus infections. Guillain-Barre syndrome is an autoimmune disease characterized by ascending paralysis and polyneuropathy that could occur during the acute or convalescent phases of ZIKV infection (Cao-Lormeau et al., 2016). During pregnancy (especially in the first trimester), ZIKV infections of fetus have been associated with a variety of clinical manifestations, now collectively known as congenital Zika syndrome, including microcephaly, craniofacial disproportion, spasticity, seizures, ocular abnormalities, cerebral calcification, and miscarriage (Rasmussen et al., 2016). Moreover, the disease spectrum of congenital Zika syndrome is expected to grow as some of the infected babies with a normal head circumference may manifest new disease symptoms as they develop; clinical and epidemiological studies are ongoing to uncover the prognosis of these congenitally infected baby patients (Costello et al., 2016). The molecular mechanisms of ZIKV-mediated Guillain-Barre syndrome and congenital malformations remain to be determined. One of the notable driving forces for the congenital Zika syndrome could be the neurotropic nature of ZIKV infection that preferentially targets cortical neural progenitor cells and, to a lesser extent, neuronal cells in other stages of maturity (Tang et al., 2016).

Despite the unprecedented progress of Zika research, studies of pathology related to ZIKV infection have been limited in humans, mainly due to the fact that about 80% of the infected individuals are asymptomatic, and for those who are symptomatic, most patients only exhibit mild diseases that do not warrant tissue samplings for histopathological investigation. Even for the small proportion of infected patients with severe clinical symptoms, pathological changes in tissues might be mild or nonspecific. Therefore, it is important to develop animal models that can recapitulate human diseases of ZIKV infection. A number of groups have successfully established mouse and non-human primate models for ZIKV, as summarized in a recent review (Morrison and Diamond, 2017). Among the various mouse models that are currently available to study ZIKV vertical transmission, none is able to develop a congenitally infected fetus to birth and adulthood; this is because the infected pups usually die before or soon after birth. Thus, the current mouse models do not allow study adulthood sequelae of congenital ZIKV infection.

In this issue of EBioMedicine, Cui and colleagues report a novel mouse model to address the above critical gap of ZIKV animal model. The new model allows ZIKV-infected fetuses develop to the full term of gestation, deliver and grow the pups into adulthood, during which anatomical defects and behavior sequelae of congenital infection could be studied (Cui et al., 2017). Compared with all previous ZIKV pregnancy models, the current model infects pregnant C57BL/6 mice on embryonic day 15 (E15) with 500 plaque-forming units of ZIKV through an amniotic fluid injection. Remarkably, this mouse model recapitulates several clinical manifestations of congenital Zika syndrome, including reduced brain volume, thinner cortex, visual dysfunction and motor incoordination, and corresponding anatomical defects in visual circuits and cerebellum, and intracranial calcification.

The congenitally ZIKV-infected pubertal model has many applications in both basic and translational research. For basic research, the model has provided an experimental system to investigate the causative mechanism(s) of congenital ZIKV infection and disease development. A number of future directions could be pursued. What are the spatial and temporal kinetics of viral infection and immune response in this congenitally infected pubertal model? How much does viral infection per se contribute to the observed pathological outcome? If so, do the acute and/or persistent stages of viral infection affect different disease aspects during fetus development? What role does ZIKV-induced immunological response play in disease development? Are there other prognostic disease symptoms as the congenitally infected mice grow older? For translational research, the pubertal model could be used to test potential therapeutics. Two types of therapeutics could be conceived for testing: (i) drugs that repair and regenerate damaged nervous system, and (ii) direct antiviral agents that suppress viral replication (Xie et al., 2016). In addition, as several promising ZIKV vaccines are advancing into clinical trials (Fernandez and Diamond, 2017, Shan et al., 2017), the pubertal mouse model could be applied to testing their efficacy for protection of adulthood sequelae of congenital ZIKV infection.

Conflict of Interests

The authors declare no conflicts of interest.