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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

Brain histopathology after ZIKV infection.Cortical tissue revealing meningeal infiltration by a mixture of neutrophils and mononuclear cells. A small amount of a similar infiltrate is seen surrounding an adjacent vessel (A). Cerebral neuropil section will cellular pyknosis, scattered neutrophils, and perivascular neutrophilic infiltration (B). Apparent necrosis and neutrophil invasion of primordial germ cell region (C). Scale bar, 20 μm. Data are representative of two independent experiments (n = 4 and 5).
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pntd.0004682.g005: Brain histopathology after ZIKV infection.Cortical tissue revealing meningeal infiltration by a mixture of neutrophils and mononuclear cells. A small amount of a similar infiltrate is seen surrounding an adjacent vessel (A). Cerebral neuropil section will cellular pyknosis, scattered neutrophils, and perivascular neutrophilic infiltration (B). Apparent necrosis and neutrophil invasion of primordial germ cell region (C). Scale bar, 20 μm. Data are representative of two independent experiments (n = 4 and 5).

Mentions: Examination of the brain, revealed significant histopathology associated with ZIKV infection. The most prominent histopathological feature included neutrophil infiltration of the hippocampus, which at times was associated with degenerate neurons and glia. A prominent linear focus of neutrophil invasion adjacent to the choroid plexus also was observed (Fig 4B), and cortical tissue from the brain showed meningeal infiltration by a mixture of neutrophils and mononuclear cells (Fig 5A). A small amount of a similar infiltrate also was observed surrounding an adjacent small vessel in the cortical tissue. Within the neuropil there were neutrophils and foci of necrotic cellular debris that may have been neurons or glia. This may be indicative of viral replication, because it has been previously demonstrated that ZIKV replicates in both neurons and astroglial cells [17] but confirmation will require further studies/confirmation. In addition, microscopic examination of a section of cerebral neuropil (Fig 5B) revealed cellular pyknosis, scattered neutrophils, and perivascular neutrophilic infiltration. Finally, there was apparent necrosis and neutrophilic invasion of primordial germ cell regions (Fig 5C). In sum, ZIKV caused severe brain pathology in AG129 mice, potentially emulating hallmark features of human fetal ZIKV infection. At the very least, these data warrant further exploration into the feasibility of this infection model in relationship to human disease.


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)

Brain histopathology after ZIKV infection.Cortical tissue revealing meningeal infiltration by a mixture of neutrophils and mononuclear cells. A small amount of a similar infiltrate is seen surrounding an adjacent vessel (A). Cerebral neuropil section will cellular pyknosis, scattered neutrophils, and perivascular neutrophilic infiltration (B). Apparent necrosis and neutrophil invasion of primordial germ cell region (C). 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.g005: Brain histopathology after ZIKV infection.Cortical tissue revealing meningeal infiltration by a mixture of neutrophils and mononuclear cells. A small amount of a similar infiltrate is seen surrounding an adjacent vessel (A). Cerebral neuropil section will cellular pyknosis, scattered neutrophils, and perivascular neutrophilic infiltration (B). Apparent necrosis and neutrophil invasion of primordial germ cell region (C). Scale bar, 20 μm. Data are representative of two independent experiments (n = 4 and 5).
Mentions: Examination of the brain, revealed significant histopathology associated with ZIKV infection. The most prominent histopathological feature included neutrophil infiltration of the hippocampus, which at times was associated with degenerate neurons and glia. A prominent linear focus of neutrophil invasion adjacent to the choroid plexus also was observed (Fig 4B), and cortical tissue from the brain showed meningeal infiltration by a mixture of neutrophils and mononuclear cells (Fig 5A). A small amount of a similar infiltrate also was observed surrounding an adjacent small vessel in the cortical tissue. Within the neuropil there were neutrophils and foci of necrotic cellular debris that may have been neurons or glia. This may be indicative of viral replication, because it has been previously demonstrated that ZIKV replicates in both neurons and astroglial cells [17] but confirmation will require further studies/confirmation. In addition, microscopic examination of a section of cerebral neuropil (Fig 5B) revealed cellular pyknosis, scattered neutrophils, and perivascular neutrophilic infiltration. Finally, there was apparent necrosis and neutrophilic invasion of primordial germ cell regions (Fig 5C). In sum, ZIKV caused severe brain pathology in AG129 mice, potentially emulating hallmark features of human fetal ZIKV infection. At the very least, these data warrant further exploration into the feasibility of this infection model in relationship to human disease.

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