Producing Neurological Symptoms in Mouse Model of Zika Virus


     
Producing Neurological Symptoms in Mouse Model of Zika Virus

Severity of 2015 Outbreak Fuels Research

Zika virus (ZIKV) is a flavivirus transmitted primarily through mosquito bites. It was first discovered in 1947, and outbreaks described from the 1960s through 1980s were associated with mild illness in affected humans. A Brazilian outbreak in 2015, however, has been associated with Guillain-Barré syndrome and other neurological disorders in infected humans, along with fetal abnormalities such as stillbirth and microcephaly.

As of today, the outbreak has spread to other countries, including the United States.

Control efforts have focused primarily on the mosquito vectors, Aedes aegypti and Aedes albopictus, and prevention of mosquito bites. As there are no specific treatments available for Zika, significant scientific resources are currently focused on ZIKV research.

Existing Animal Models Slow ZIKV Research

ZIKV research encompasses different aims, from understanding the progression of the disease, including in pregnancy, through testing vaccines and antiviral drugs. A suitable animal model is critical to understanding this disease and developing treatments.

Since 2015, several animal models have been used for ZIKV studies, including:

This heavy reliance on NHP and genetically engineered animal models not only increases the cost of research, but raises possible issues with the translatability. Insights from studies conducted on immunocompromised, genetically engineered mouse models of Zika virus may not apply to immunocompetent humans of the disease.

A more affordable and translatable mouse model of Zika pathology would accelerate the development of treatment options, but our most frequently used biomedical research models proved resistant to infection.

A New Mouse Model of Zika Virus Infection

C57BL/6 mice, the most commonly used inbred strain in biomedical research, have previously been reported as resistant to ZIKV. FDA researchers recently discovered a means of bypassing this resistance, establishing an immunocompetent b6 mouse model of Zika pathology for further investigation.

Their study demonstrates a neonatal infection method which results in CNS infection and neurologic symptoms. According to the authors, "This model does not address transplacental transmission of virus from mother to fetus or adult transmission, however it offers an immunocompetent symptomatic mouse model for ZIKV infections that may prove useful to understand the long term effects of ZIKV infection."

Symptoms B6 WT IFNAR KO
Hyperactivity ++ -
Wide stance + +
Stagger march
Start/stop
++ -
Limb collapse ++ -
Seizure ++ -
Bilateral flaccid hind limb paralysis - ++
Tremors + +
Death - +++
Note: Above table adapted from PLoS Pathog. 12(11):e1006004.
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References:
Rossi SL, Tesh RB, Azar SR, Muruato AE, Hanley KA, Auguste AJ, Langsjoen RM, Paessler S, Vasilakis N, Weaver SC. (2016) Characterization of a Novel Murine Model to Study Zika Virus. Am J Trop Med Hyg. 94(6):1362-9.
Lazear HM, Govero J, Smith AM, Platt DJ, Fernandez E, Miner JJ, Diamond MS. (2016) A Mouse Model of Zika Virus Pathogenesis. Cell Host Microbe. 19(5):720-30.
Cugola FR, Fernandes IR, Russo FB, Freitas BC, Dias JL, Guimarães KP, Benazzato C, Almeida N, Pignatari GC, Romero S, Polonio CM, Cunha I, Freitas CL, Brandão WN, Rossato C, Andrade DG, Faria Dde P, Garcez AT, Buchpigel CA, Braconi CT, Mendes E, Sall AA, Zanotto PM, Peron JP, Muotri AR, Beltrão-Braga PC. (2016) The Brazilian Zika virus strain causes birth defects in experimental models. Nature. 534(7606):267-71.
Manangeeswaran M, Ireland DD, Verthelyi D. (2016) Zika (PRVABC59) Infection Is Associated with T cell Infiltration and Neurodegeneration in CNS of Immunocompetent Neonatal C57Bl/6 Mice. PLoS Pathog. 12(11):e1006004.