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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

ZIKV causes mortality and morbidity in AG129 mice.Kaplan-Meier curves illustrate the susceptibility of AG129 mice to ZIKV. Young mice were inoculated f.p. with several doses (n = 3 for doses 105−103 PFU and n = 6 for doses 10 and 1 PFU; 102 PFU was done as two separate independent replicates with n = 3 for each) of ZIKV (A). All mice challenged with 104−1 PFU succumbed 8 d PI. Young (n = 4) and adult mice (n = 6) were inoculated f.p. with 105 PFU of ZIKV (B). Mice were monitored until day 10 PI. Changes in weight were calculated daily for ZIKV- and mock-infected mice (C). Error bars represent standard error of the mean.
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pntd.0004682.g001: ZIKV causes mortality and morbidity in AG129 mice.Kaplan-Meier curves illustrate the susceptibility of AG129 mice to ZIKV. Young mice were inoculated f.p. with several doses (n = 3 for doses 105−103 PFU and n = 6 for doses 10 and 1 PFU; 102 PFU was done as two separate independent replicates with n = 3 for each) of ZIKV (A). All mice challenged with 104−1 PFU succumbed 8 d PI. Young (n = 4) and adult mice (n = 6) were inoculated f.p. with 105 PFU of ZIKV (B). Mice were monitored until day 10 PI. Changes in weight were calculated daily for ZIKV- and mock-infected mice (C). Error bars represent standard error of the mean.

Mentions: In initial studies, AG129 mice were tested for susceptibility to infection with ZIKV, which was originally isolated from a traveler that visited French Polynesia in 2013. Both intraperitoneal inoculation (i.p., n = 5) and foot pad inoculation (f.p., n = 4) of three- to four-week-old AG129 mice (young mice) with 105 PFU of ZIKV caused rapidly fatal infection, i.e., both groups were humanely euthanized on day 7 when all mice appeared moribund. In subsequent testing with young mice (n = 3 mice for doses 105−103 PFU and n = 6 for doses 102−1 PFU), 100% mortality was observed for all doses ranging from 105 to 1 PFU (Fig 1A). Likewise, 105 PFU of ZIKV also resulted in 100% mortality in eight-week-old mice (adult mice, n = 6, Fig 1B). Regardless of dose or age, AG129 mice exhibited signs of illness by four to five days PI, including weight loss, lethargy, and hunched posture. Interestingly, none of the mice that succumbed to infection developed signs of paralysis during the entire observation period. Still, animals deteriorated rapidly, becoming immobile and weak, and were typically euthanized seven to eight days PI. As a measurement of mouse morbidity, weight change was monitored daily during acute infection. In contrast to uninfected age-matched controls, which did not exhibit weight loss, ZIKV-infected mice lost weight starting on day five PI (Fig 1C), at approximately the same time as clinical signs were visually noted. Mouse weight decreased to 80% or lower even for mice infected with the lowest dose inoculum of 1 PFU. Weight loss data were consistent with survival data.


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)

ZIKV causes mortality and morbidity in AG129 mice.Kaplan-Meier curves illustrate the susceptibility of AG129 mice to ZIKV. Young mice were inoculated f.p. with several doses (n = 3 for doses 105−103 PFU and n = 6 for doses 10 and 1 PFU; 102 PFU was done as two separate independent replicates with n = 3 for each) of ZIKV (A). All mice challenged with 104−1 PFU succumbed 8 d PI. Young (n = 4) and adult mice (n = 6) were inoculated f.p. with 105 PFU of ZIKV (B). Mice were monitored until day 10 PI. Changes in weight were calculated daily for ZIKV- and mock-infected mice (C). Error bars represent standard error of the mean.
© Copyright Policy
Related In: Results  -  Collection

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

pntd.0004682.g001: ZIKV causes mortality and morbidity in AG129 mice.Kaplan-Meier curves illustrate the susceptibility of AG129 mice to ZIKV. Young mice were inoculated f.p. with several doses (n = 3 for doses 105−103 PFU and n = 6 for doses 10 and 1 PFU; 102 PFU was done as two separate independent replicates with n = 3 for each) of ZIKV (A). All mice challenged with 104−1 PFU succumbed 8 d PI. Young (n = 4) and adult mice (n = 6) were inoculated f.p. with 105 PFU of ZIKV (B). Mice were monitored until day 10 PI. Changes in weight were calculated daily for ZIKV- and mock-infected mice (C). Error bars represent standard error of the mean.
Mentions: In initial studies, AG129 mice were tested for susceptibility to infection with ZIKV, which was originally isolated from a traveler that visited French Polynesia in 2013. Both intraperitoneal inoculation (i.p., n = 5) and foot pad inoculation (f.p., n = 4) of three- to four-week-old AG129 mice (young mice) with 105 PFU of ZIKV caused rapidly fatal infection, i.e., both groups were humanely euthanized on day 7 when all mice appeared moribund. In subsequent testing with young mice (n = 3 mice for doses 105−103 PFU and n = 6 for doses 102−1 PFU), 100% mortality was observed for all doses ranging from 105 to 1 PFU (Fig 1A). Likewise, 105 PFU of ZIKV also resulted in 100% mortality in eight-week-old mice (adult mice, n = 6, Fig 1B). Regardless of dose or age, AG129 mice exhibited signs of illness by four to five days PI, including weight loss, lethargy, and hunched posture. Interestingly, none of the mice that succumbed to infection developed signs of paralysis during the entire observation period. Still, animals deteriorated rapidly, becoming immobile and weak, and were typically euthanized seven to eight days PI. As a measurement of mouse morbidity, weight change was monitored daily during acute infection. In contrast to uninfected age-matched controls, which did not exhibit weight loss, ZIKV-infected mice lost weight starting on day five PI (Fig 1C), at approximately the same time as clinical signs were visually noted. Mouse weight decreased to 80% or lower even for mice infected with the lowest dose inoculum of 1 PFU. Weight loss data were consistent with survival data.

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