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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

Comparative histological imaging of skeletal muscle and brain after mock infection and infection with ZIKV.Musculature from the posterior rear limb of a ZIKV-infected mouse revealing nuclear rowing as well as degenerate muscle fibers and infiltrating inflammatory cells (A). Hippocampal section from a ZIKV-infected mouse revealing neutrophilic infiltration (B). Musculature from the same site in a mock-infected mouse (C) A section of hippocampus in the brain of mock-infected mouse (D). Scale bar, 20 μm. Data are representative of two independent experiments (n = 4 and 5).
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pntd.0004682.g004: Comparative histological imaging of skeletal muscle and brain after mock infection and infection with ZIKV.Musculature from the posterior rear limb of a ZIKV-infected mouse revealing nuclear rowing as well as degenerate muscle fibers and infiltrating inflammatory cells (A). Hippocampal section from a ZIKV-infected mouse revealing neutrophilic infiltration (B). Musculature from the same site in a mock-infected mouse (C) A section of hippocampus in the brain of mock-infected mouse (D). Scale bar, 20 μm. Data are representative of two independent experiments (n = 4 and 5).

Mentions: Because ZIKV has been associated with microcephaly and recently it was confirmed that ZIKV was present in fetal brain tissue [6], we undertook a comparative histological analysis of brain and other tissues from ZIKV-infected and mock-infected AG129 mice, specifically surveying for obvious morphological changes associated with ZIKV infection. Surprisingly, examination of hematoxylin and eosin-stained semi-thin sections did not reveal any obvious tissue damage associated with ZIKV infection in the majority of tissues examined (e.g., heart, liver, spleen, intestine, kidney, and lung) and looked similar to mock-infected controls. However, examination of the musculature from the posterior rear limb of a ZIKV-infected mouse revealed multi-focal myofiber degeneration and necrosis with inflammatory cell infiltration, nuclear rowing, and attempted regeneration (Fig 4A).


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)

Comparative histological imaging of skeletal muscle and brain after mock infection and infection with ZIKV.Musculature from the posterior rear limb of a ZIKV-infected mouse revealing nuclear rowing as well as degenerate muscle fibers and infiltrating inflammatory cells (A). Hippocampal section from a ZIKV-infected mouse revealing neutrophilic infiltration (B). Musculature from the same site in a mock-infected mouse (C) A section of hippocampus in the brain of mock-infected mouse (D). Scale bar, 20 μm. Data are representative of two independent experiments (n = 4 and 5).
© Copyright Policy
Related In: Results  -  Collection

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

pntd.0004682.g004: Comparative histological imaging of skeletal muscle and brain after mock infection and infection with ZIKV.Musculature from the posterior rear limb of a ZIKV-infected mouse revealing nuclear rowing as well as degenerate muscle fibers and infiltrating inflammatory cells (A). Hippocampal section from a ZIKV-infected mouse revealing neutrophilic infiltration (B). Musculature from the same site in a mock-infected mouse (C) A section of hippocampus in the brain of mock-infected mouse (D). Scale bar, 20 μm. Data are representative of two independent experiments (n = 4 and 5).
Mentions: Because ZIKV has been associated with microcephaly and recently it was confirmed that ZIKV was present in fetal brain tissue [6], we undertook a comparative histological analysis of brain and other tissues from ZIKV-infected and mock-infected AG129 mice, specifically surveying for obvious morphological changes associated with ZIKV infection. Surprisingly, examination of hematoxylin and eosin-stained semi-thin sections did not reveal any obvious tissue damage associated with ZIKV infection in the majority of tissues examined (e.g., heart, liver, spleen, intestine, kidney, and lung) and looked similar to mock-infected controls. However, examination of the musculature from the posterior rear limb of a ZIKV-infected mouse revealed multi-focal myofiber degeneration and necrosis with inflammatory cell infiltration, nuclear rowing, and attempted regeneration (Fig 4A).

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