New Zika Mouse Model Provides Much-needed Insight on the Virus

Researchers from the National Infection Service at Public Health England (PHE) in the UK may have identified the perfect platform for trials of future vaccines and antivirals for the management of Zika.

Zika, the mosquito-borne pathogen that has been at the center of a public health crisis in the Americas (particularly in Brazil and the Caribbean) for nearly two years, has been associated with multiple health complications, including Guillain-Barré syndrome and microcephaly. Infectious disease researchers have been working furiously to develop control measures to manage outbreaks, even experimenting with bacteria known to kill the mosquito vector that transmits it.

However, a suitable animal model for testing pharmacologic approaches has proved elusive—until now.

“[A Zika virus] disease model is acutely needed, given the immediate health concerns and the lack of interventions available to respond to the current outbreak… in South America,” study co-author Stuart D. Dowall, PhD, project team leader, virology, PHE, told Contagion. “Indeed we decided to publish [our] work online as soon as it was completed and before it had undergone formal peer review [to make] it available to the scientific and public health community as soon as possible. [Our hope is] this work will build new research efforts to help scientists understand the ways in which Zika virus is transmitted to the unborn fetus, how it is able to establish microcephaly, and, in turn, how new interventions can be developed.”

The team of researchers from PHE, who published their findings on May 5th in the journal PLOS Neglected Tropical Diseases, studied the effects of Zika virus infection in type-I interferon receptor deficient (A129) and parent strain (129Sv/Ev) mice, using another group of parent strain (129Sv/Ev) mice as controls. They injected each of the mice in the experiment with Zika virus strain MP1751, which was isolated from Aedes africanus mosquitoes. The virus was “transmitted” to the mice models subcutaneously, to mimic a mosquito bite. Viral RNA was tested via real-time polymerase chain reaction (PCR) assay.

The PHE team found that all A129 animals met “humane clinical endpoints six days after challenge” with Zika virus, and that wild-type 129Sv/Ev mice all survived the 14-day length of the study, as did the control animals. When they compared the weight of the mice in each group, they noticed that the Zika-challenged A129 mice began losing weight rapidly, while the other groups experienced a gradual increase over the course of the study, indicating they were healthy. In addition, the A129 mice experienced a gradual increase in body temperature until Day 4 post-challenge, followed by a rapid decrease. Overall, the A129 ZIKV-challenged mice were the only ones which exhibited signs of disease post-challenge, with signs first identified on Day 5 and increasing until humane endpoints were met on Day 6.

Furthermore, viral RNA levels were detectable in the blood and tissue (including the brain, ovaries, spleen, and liver) of Zika-challenged A129 and 129Sv/Ev mice culled at Day 3 post-challenge and Days 6 (A129) or 7 (129Sv/Ev) post-challenge. The data demonstrate that the A129 mice are highly susceptible to Zika virus.

“This new disease model will make an immediate contribution to research efforts on antiviral therapies for Zika virus infection, including work on vaccines,” Dr. Dowall said. “The Zika-related pathological changes observed in our model, will help with identifying the cellular and brain targets of the virus and how it causes disease. This will enable researchers to focus on the molecular basis of disease and aid in the rational design of antiviral compounds. Basic questions about flavivirus biology including the phenomenon of antibody enhanced infection can also be assessed in this model. Importantly, the model will allow work to be planned and coordinated in a strict, regulated and efficient manner for maximum public health benefit.”

Brian P. Dunleavy is a medical writer and editor based in New York. His work has appeared in numerous healthcare-related publications. He is the former editor of Infectious Disease Special Edition.