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Characterization of Lethal Zika Virus Infection in AG129 Mice.

Aliota MT, Caine EA, Walker EC, Larkin KE, Camacho E, Osorio JE - PLoS Negl Trop Dis (2016)

Bottom Line: Here, we describe a small animal model for wild-type ZIKV of the Asian lineage.Rapid viremic dissemination was observed in visceral organs and brain; but only was associated with severe pathologies in the brain and muscle.This newly developed Zika disease model can be exploited to identify determinants of ZIKV virulence and reveal molecular mechanisms that control the virus-host interaction, providing a framework for rational design of acute phase therapeutics and for vaccine efficacy testing.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.

ABSTRACT

Background: Mosquito-borne Zika virus (ZIKV) typically causes a mild and self-limiting illness known as Zika fever, which often is accompanied by maculopapular rash, headache, and myalgia. During the current outbreak in South America, ZIKV infection during pregnancy has been hypothesized to cause microcephaly and other diseases. The detection of ZIKV in fetal brain tissue supports this hypothesis. Because human infections with ZIKV historically have remained sporadic and, until recently, have been limited to small-scale epidemics, neither the disease caused by ZIKV nor the molecular determinants of virulence and/or pathogenicity have been well characterized. Here, we describe a small animal model for wild-type ZIKV of the Asian lineage.

Methodology/principal findings: Using mice deficient in interferon α/β and Ɣ receptors (AG129 mice), we report that these animals were highly susceptible to ZIKV infection and disease, succumbing within seven to eight days. Rapid viremic dissemination was observed in visceral organs and brain; but only was associated with severe pathologies in the brain and muscle. Finally, these results were consistent across challenge routes, age of mice, and inoculum doses. These data represent a mouse model for ZIKV that is not dependent on adapting ZIKV to intracerebral passage in mice.

Conclusions/significance: Foot pad injection of AG129 mice with ZIKV represents a biologically relevant model for studying ZIKV infection and disease development following wild-type virus inoculation without the requirement for adaptation of the virus or intracerebral delivery of the virus. This newly developed Zika disease model can be exploited to identify determinants of ZIKV virulence and reveal molecular mechanisms that control the virus-host interaction, providing a framework for rational design of acute phase therapeutics and for vaccine efficacy testing.

No MeSH data available.


Related in: MedlinePlus

Mice have high tissue viral loads 7 days post infection.Mice were infected with 105 PFU of ZIKV, euthanized at day seven (young) or day eight (adult), and tissue viral loads were determined by qRT-PCR as described in the text. Closed symbols indicate young mice (n = 3), open symbols indicate adult mice (n = 4), and the dotted line represents the limit of detection for the assay.
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pntd.0004682.g003: Mice have high tissue viral loads 7 days post infection.Mice were infected with 105 PFU of ZIKV, euthanized at day seven (young) or day eight (adult), and tissue viral loads were determined by qRT-PCR as described in the text. Closed symbols indicate young mice (n = 3), open symbols indicate adult mice (n = 4), and the dotted line represents the limit of detection for the assay.

Mentions: In order to characterize ZIKV-induced disease further, we measured viral titer in serum from young AG129 mice infected with 105, 103, and 102 PFU of ZIKV and adult AG129 mice infected with 105 PFU (Fig 2). In young mice, viral titer in the serum was observed to peak on day two in all animals infected with ZIKV. No significant differences in viral titers were observed between inoculum doses (p>0.05). In adult mice, viral titer in the serum also peaked on day two and there was no significant difference in viral titers between young and old mice (p>0.05). We also attempted to determine systemic spread of the virus using qRT-PCR. In the absence of type I and II IFN responses, infection with ZIKV led to rapid viral dissemination, most likely by infecting and commandeering migratory dendritic cells and/or macrophages, as has been reported for ZIKV [18] and other flaviviruses [25,26]. Viral loads were high in all tissues and were comparable between young and old mice receiving 105 PFU of ZIKV (Fig 3). The highest viral loads were observed in brains from young mice (e.g., one mouse had 11.69 log10 viral copies/g in the brain). Because the animals were not perfused with phosphate-buffered saline prior to tissue collection, some virus detection may be from blood; however, no detectable serum viremia was observed in mice after six days PI.


Characterization of Lethal Zika Virus Infection in AG129 Mice.

Aliota MT, Caine EA, Walker EC, Larkin KE, Camacho E, Osorio JE - PLoS Negl Trop Dis (2016)

Mice have high tissue viral loads 7 days post infection.Mice were infected with 105 PFU of ZIKV, euthanized at day seven (young) or day eight (adult), and tissue viral loads were determined by qRT-PCR as described in the text. Closed symbols indicate young mice (n = 3), open symbols indicate adult mice (n = 4), and the dotted line represents the limit of detection for the assay.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4836712&req=5

pntd.0004682.g003: Mice have high tissue viral loads 7 days post infection.Mice were infected with 105 PFU of ZIKV, euthanized at day seven (young) or day eight (adult), and tissue viral loads were determined by qRT-PCR as described in the text. Closed symbols indicate young mice (n = 3), open symbols indicate adult mice (n = 4), and the dotted line represents the limit of detection for the assay.
Mentions: In order to characterize ZIKV-induced disease further, we measured viral titer in serum from young AG129 mice infected with 105, 103, and 102 PFU of ZIKV and adult AG129 mice infected with 105 PFU (Fig 2). In young mice, viral titer in the serum was observed to peak on day two in all animals infected with ZIKV. No significant differences in viral titers were observed between inoculum doses (p>0.05). In adult mice, viral titer in the serum also peaked on day two and there was no significant difference in viral titers between young and old mice (p>0.05). We also attempted to determine systemic spread of the virus using qRT-PCR. In the absence of type I and II IFN responses, infection with ZIKV led to rapid viral dissemination, most likely by infecting and commandeering migratory dendritic cells and/or macrophages, as has been reported for ZIKV [18] and other flaviviruses [25,26]. Viral loads were high in all tissues and were comparable between young and old mice receiving 105 PFU of ZIKV (Fig 3). The highest viral loads were observed in brains from young mice (e.g., one mouse had 11.69 log10 viral copies/g in the brain). Because the animals were not perfused with phosphate-buffered saline prior to tissue collection, some virus detection may be from blood; however, no detectable serum viremia was observed in mice after six days PI.

Bottom Line: Here, we describe a small animal model for wild-type ZIKV of the Asian lineage.Rapid viremic dissemination was observed in visceral organs and brain; but only was associated with severe pathologies in the brain and muscle.This newly developed Zika disease model can be exploited to identify determinants of ZIKV virulence and reveal molecular mechanisms that control the virus-host interaction, providing a framework for rational design of acute phase therapeutics and for vaccine efficacy testing.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.

ABSTRACT

Background: Mosquito-borne Zika virus (ZIKV) typically causes a mild and self-limiting illness known as Zika fever, which often is accompanied by maculopapular rash, headache, and myalgia. During the current outbreak in South America, ZIKV infection during pregnancy has been hypothesized to cause microcephaly and other diseases. The detection of ZIKV in fetal brain tissue supports this hypothesis. Because human infections with ZIKV historically have remained sporadic and, until recently, have been limited to small-scale epidemics, neither the disease caused by ZIKV nor the molecular determinants of virulence and/or pathogenicity have been well characterized. Here, we describe a small animal model for wild-type ZIKV of the Asian lineage.

Methodology/principal findings: Using mice deficient in interferon α/β and Ɣ receptors (AG129 mice), we report that these animals were highly susceptible to ZIKV infection and disease, succumbing within seven to eight days. Rapid viremic dissemination was observed in visceral organs and brain; but only was associated with severe pathologies in the brain and muscle. Finally, these results were consistent across challenge routes, age of mice, and inoculum doses. These data represent a mouse model for ZIKV that is not dependent on adapting ZIKV to intracerebral passage in mice.

Conclusions/significance: Foot pad injection of AG129 mice with ZIKV represents a biologically relevant model for studying ZIKV infection and disease development following wild-type virus inoculation without the requirement for adaptation of the virus or intracerebral delivery of the virus. This newly developed Zika disease model can be exploited to identify determinants of ZIKV virulence and reveal molecular mechanisms that control the virus-host interaction, providing a framework for rational design of acute phase therapeutics and for vaccine efficacy testing.

No MeSH data available.


Related in: MedlinePlus