Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2016 May 5;10(5):e0004658.
doi: 10.1371/journal.pntd.0004658. eCollection 2016 May.

A Susceptible Mouse Model for Zika Virus Infection

Stuart D Dowall  1 , Victoria A Graham  1 , Emma Rayner  1 , Barry Atkinson  1 , Graham Hall  1 , Robert J Watson  1 , Andrew Bosworth  1 , Laura C Bonney  1 , Samantha Kitchen  1 , Roger Hewson  1
Affiliations

A Susceptible Mouse Model for Zika Virus Infection

Stuart D Dowall et al. PLoS Negl Trop Dis. .

Abstract

Zika virus (ZIKV) is a mosquito-borne pathogen which has recently spread beyond Africa and into Pacific and South American regions. Despite first being detected in 1947, very little information is known about the virus, and its spread has been associated with increases in Guillain-Barre syndrome and microcephaly. There are currently no known vaccines or antivirals against ZIKV infection. Progress in assessing interventions will require the development of animal models to test efficacies; however, there are only limited reports on in vivo studies. The only susceptible murine models have involved intracerebral inoculations or juvenile animals, which do not replicate natural infection. Our report has studied the effect of ZIKV infection in type-I interferon receptor deficient (A129) mice and the parent strain (129Sv/Ev) after subcutaneous challenge in the lower leg to mimic a mosquito bite. A129 mice developed severe symptoms with widespread viral RNA detection in the blood, brain, spleen, liver and ovaries. Histological changes were also striking in these animals. 129Sv/Ev mice developed no clinical symptoms or histological changes, despite viral RNA being detectable in the blood, spleen and ovaries, albeit at lower levels than those seen in A129 mice. Our results identify A129 mice as being highly susceptible to ZIKV and thus A129 mice represent a suitable, and urgently required, small animal model for the testing of vaccines and antivirals.

PubMed Disclaimer

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. ZIKV is virulent to IFN-α/β receptor deficient mice (A129) whilst wild-type mice (129Sv/Ev) do not exhibit signs of disease.
A129 (closed circle) and 129Sv/Ev (closed triangle) mice were subcutaneously inoculated in the lower leg with 106 pfu ZIKV and compared to PBS mock-infected A129 (open circle) and 129Sv/Ev (open triangle) groups. (A) Survival analysis of groups presented as Kaplan-Meier survival curves. (B) Weight changes compared to the day of challenge. (C) Temperature changes compared to the day of challenge. (D) Clinical scores of animals. Graphs B-D show the mean values with errors bars denoting standard error. Group sizes were: n = 8 (A129, ZIKV-challenged); n = 8 to day 7 and n = 4 from days 8–14 (129Sv/Ev, ZIKV-challenged); and n = 3 (A129 and 129Sv/Ev, PBS mock-challenged).
Fig 2
Fig 2. Levels of ZIKV viral RNA in blood, brain, ovary, spleen and liver samples in IFN-α/β receptor-deficient (A129) and wild-type (129Sv/Ev) mice post-challenge.
Mice were subcutaneously challenged in the lower leg with 106 pfu ZIKV. At day 3 and day 6 (A129) or 7 (129Sv/Ev) mice were culled to assess viral load within the circulation and at local sites. Results are denoted as the genome equivalent per ml of blood or per g of tissue. Bars show mean viral RNA levels with error bars denoting standard error. Group sizes were: n = 4 (A129 and 129Sv/Ev, day 3 post-challenge); n = 8 (A129, day 6 post-challenge); and n = 4 (129Sv/Ev, day 7 post-challenge).
Fig 3
Fig 3. Pathological findings in ZIKV challenged A129 mice.
(A) Brain. Animal 23842 (A129, ZIKV-challenged, day 6). Scattered, nuclear fragment in the neuropil of the cerebral cortex (circled). Inset, higher magnification of nuclear debris. (B) Brain. Animal 23811 (A129, ZIKV-challenged, day 6). Lymphocyte infiltration of meninges and perivascular cuffing of meningeal vessels surrounding the cerebral cortex. Inset, degenerate and fragmented nuclei. (C) Brain. Animal 23962 (A129, ZIKV-challenged, day 6). Prominent, perivascular cuffing of small vessels in the neuropil, with infiltration of polymorphonuclear leukocytes (arrows) and presence of scattered, nuclear fragments (arrowheads). H&E. (D) Brain. Animal 23842 (A129, ZIKV-challenged, day 6). Scattered, shrunken, hyper-eosinophilic cells (arrows) amongst the neurons of the hippocampus. Inset, Animal 23798 (129Sv/Ev, PBS, day 14). Normal neurons. (E) Spleen. Animal 23800 (A129, ZIKV-challenged, day 6). Poorly defined white pulp with large, irregular germinal centres. Inset, Animal 23798 (129Sv/Ev, PBS, day 14). Well defined germinal centres within the white pulp (F) Spleen, red pulp. Animal 23800 (A129, ZIKV-challenged, day 6). Numerous, mature neutrophils within the red pulp (circled). (F) Liver. Animal 23836 (A129, ZIKV-challenged, day 6). Small foci of extra-medullary haematopoiesis scattered randomly throughout the parenchyma.
See this image and copyright information in PMC

Comment in

  • Zika Virus: A New Animal Model for an Arbovirus.
    Aman MJ, Kashanchi F. Aman MJ, et al. PLoS Negl Trop Dis. 2016 May 5;10(5):e0004702. doi: 10.1371/journal.pntd.0004702. eCollection 2016 May. PLoS Negl Trop Dis. 2016. PMID: 27149628 Free PMC article. No abstract available.

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Dick G.W., Kitchen S.F., and Haddow A.J., Zika virus. I. Isolations and serological specificity. Trans R Soc Trop Med Hyg, 1952. 46(5): p. 509–20. - PubMed
    1. Fagbami A.H., Zika virus infections in Nigeria: virological and seroepidemiological investigations in Oyo State. J Hyg (Lond), 1979. 83(2): p. 213–9. - PMC - PubMed
    1. Darwish M.A., et al., A sero-epidemiological survey for certain arboviruses (Togaviridae) in Pakistan. Trans R Soc Trop Med Hyg, 1983. 77(4): p. 442–5. - PubMed
    1. Marchette N.J., Garcia R., and Rudnick A., Isolation of Zika virus from Aedes aegypti mosquitoes in Malaysia. Am J Trop Med Hyg, 1969. 18(3): p. 411–5. - PubMed
    1. Olson J.G., et al., Zika virus, a cause of fever in Central Java, Indonesia. Trans R Soc Trop Med Hyg, 1981. 75(3): p. 389–93. - PubMed

Publication types

Grants and funding

This work was funded by a Public Health England Grant-In-Aid project. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.