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.2017 Mar 9;13(3):e1006258.
doi: 10.1371/journal.ppat.1006258. eCollection 2017 Mar.

A novel Zika virus mouse model reveals strain specific differences in virus pathogenesis and host inflammatory immune responses

Affiliations

A novel Zika virus mouse model reveals strain specific differences in virus pathogenesis and host inflammatory immune responses

Shashank Tripathi et al. PLoS Pathog..

Abstract

Zika virus (ZIKV) is a mosquito borne flavivirus, which was a neglected tropical pathogen until it emerged and spread across the Pacific Area and the Americas, causing large human outbreaks associated with fetal abnormalities and neurological disease in adults. The factors that contributed to the emergence, spread and change in pathogenesis of ZIKV are not understood. We previously reported that ZIKV evades cellular antiviral responses by targeting STAT2 for degradation in human cells. In this study, we demonstrate that Stat2-/- mice are highly susceptible to ZIKV infection, recapitulate virus spread to the central nervous system (CNS), gonads and other visceral organs, and display neurological symptoms. Further, we exploit this model to compare ZIKV pathogenesis caused by a panel of ZIKV strains of a range of spatiotemporal history of isolation and representing African and Asian lineages. We observed that African ZIKV strains induce short episodes of severe neurological symptoms followed by lethality. In comparison, Asian strains manifest prolonged signs of neuronal malfunctions, occasionally causing death of the Stat2-/- mice. African ZIKV strains induced higher levels of inflammatory cytokines and markers associated with cellular infiltration in the infected brain in mice, which may explain exacerbated pathogenesis in comparison to those of the Asian lineage. Interestingly, viral RNA levels in different organs did not correlate with the pathogenicity of the different strains. Taken together, we have established a new murine model that supports ZIKV infection and demonstrate its utility in highlighting intrinsic differences in the inflammatory response induced by different ZIKV strains leading to severity of disease. This study paves the way for the future interrogation of strain-specific changes in the ZIKV genome and their contribution to viral pathogenesis.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1.Stat2-/- mice support ZIKV infection and recapitulate ZIKV pathogenesis and disease.
Five to six week old female WT,Stat2-/- andIfnar1-/- C57BL/6 mice (n = 5) were injected with 1,000 PFU of ZIKV strain MR766 by the subcutaneous route in the footpad. (A) Mice were weighed daily and weights are expressed as percentage of body weight prior to infection. Results shown are the mean ± standard error of the mean (SEM). Data are censored at 6 days after infection, as mice in theStat2-/- group succumbed to infection. (B) In a parallel set of mice (n = 5) lethality was monitored for 14 days. (C) Clinical signs of ZIKV infection were monitored every day in the group of animals used for survival analysis (n = 5). Clinical signs are abbreviated as HB (hunched back, reduced motility), HL1 (one hind limb paralysis), HL2 (both hind limbs paralyzed), FL (one or both front limbs paralyzed), Endpoint (loss of 25% of initial body weight or dead). The percentage of each group of mice displaying the indicated signs is shown. (D) From the group of mice used to monitor body weight loss (n = 5, day 6 post infection), indicated organs were harvested and ZIKV RNA levels were measured by qRT PCR as described in methods. Error bars represent mean ±standard deviation (SD). Y axis starts at the limit of detection of the assay.
Fig 2
Fig 2. Phylogenetic analysis and amino acid variance of selected ZIKV strains.
(A) Neighbor joining phylogenetic tree showing the position of the viral isolates used in this study (in red) in the global ZIKV diversity. (B) Percent amino acid Identity Matrix of the 5 strains used in this study. (C) Graphic representation of the pairwise amino acid changes between the strains used in this study. Each vertical line represents an amino acid difference between the two connected strains. The order of the strains is as in (A). For a detailed description of all the amino acid differences please refer to S1 File.
Fig 3
Fig 3. Comparison of weight loss and mortality induced by African and Asian ZIKV strains in mice.
Five to six week old male WT,Stat2-/- andIfnar1-/- C57BL/6 mice (n = 5) were injected with 1,000 PFU of the indicated ZIKV strain by the subcutaneous route in the footpad. (A, B) Mice were weighed daily and weights are expressed as percentage of body weight prior to infection. Results shown are the mean ± standard error of the mean (SEM). (A) Data are censored at 6 days after infection, as some mice died. (C, D) In a parallel group, male mice (n = 5) of the indicated genotype were infected with indicated ZIKV strains under similar conditions and data were combined with body weight loss group for survival analysis (total n = 10). ZIKV strains are abbreviated as UG (Uganda), SN (Senegal), ML (Malaysia), CB (Cambodia) and PR (Puerto Rico).
Fig 4
Fig 4. Comparison of neurological disease and viral RNA levels among African and Asian ZIKV strains after infection inStat2-/- mice.
(A, B) Clinical signs of ZIKV infection were monitored every day in the group of animals used for survival analysis in Fig 3 (n = 5). Clinical signs are abbreviated as HB (hunched back, reduced motility), HL1 (one hind limb paralysis), HL2 (both hind limbs paralyzed), FL (one or both front limbs paralyzed), Endpoint (loss of 25% of initial body weight or dead). The percentage of each group of mice displaying the indicated signs is shown. (A) Data represent clinical signs observed between day 3 to day 7 post infection for the Uganda strain and day 4 to day 8 post infection for the Senegal strain. (B) Data represent clinical signs induced by Asian lineage strains between day 6 to day 10 post infection. (C, D, E). Five to six week old maleStat2-/- mice (n = 5) were infected with indicated ZIKV as described in Fig 3. On day 6 post infection indicated organs were harvested and ZIKV RNA levels were measured by qRT PCR as described in methods. Error bars represent mean ±standard deviation (SD). Y axis starts at the limit of detection of the assay.
Fig 5
Fig 5. Comparison of inflammatory immune response induced by African and Asian ZIKV strains in the CNS ofStat2-/- mice.
(A, B, C) Brain tissue homogenates were prepared from the group of maleStat2-/- mice used to measure ZIKV RNA (n = 5) (Fig 4C, 4D and 4E) and a control group of age matched, mock infected maleStat2-/- mice (n = 5). Gene expression was measured by qRT PCR as described in the methods section. Fold change of the gene expression over the mock was calculated and plotted on the graphs. Data are presented as mean ±standard deviation (SD) of log 2 fold increase over mock controls. Genes are grouped into indicated functional categories. (D) In the same set of brain homogenates, indicated cytokine and chemokine levels were measured by multiplex ELISA assay, as described in the methods section. Data are presented as mean of log 2 fold increase over mock controls.
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