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A STAT1-Knockout Mouse Model for Chapare Virus Infection and Pathogenesis
Stephanie R Monticelli1,2, Ana I Kuehne1, Thomas G Batchelor1,3
1Viral Immunology Branch, Virology Division, United States Army Medical Research Institute of Infectious Disease, Ft. Detrick, Frederick, MD 21702, USA.
Insights
Researchers developed a lethal mouse model for Chapare virus (CHAPV) infection. This STAT1-deficient mouse model mimics human Chapare hemorrhagic fever (CHHF) disease, aiding future research on this dangerous arenavirus.
Area of Science:
- Virology
- Immunology
- Infectious Diseases
Background:
- Chapare virus (CHAPV) causes Chapare hemorrhagic fever (CHHF) in Bolivia, with high fatality rates and human-to-human transmission.
- The pathogenesis of CHAPV infection remains poorly understood, hindering the development of treatments and vaccines.
- A lack of suitable animal models limits research into CHAPV and related arenaviruses.
Purpose of the Study:
- To investigate the susceptibility of signal transducer and activator of transcription 1-deficient (STAT1-/-) mice to CHAPV infection.
- To establish a small-animal model that recapitulates key features of human CHAPV disease.
- To generate a mouse-adapted CHAPV variant for further study.
Main Methods:
- STAT1-/- mice were challenged with CHAPV.
- Disease progression, viral load, and tissue tropism were monitored.
- CHAPV was adapted in the brains of STAT1-/- mice to create a lethal variant.
Main Results:
- CHAPV challenge caused partial lethality in STAT1-/- mice with a biphasic disease course.
- Initial viral replication occurred in the spleen and liver, followed by central nervous system (CNS) involvement.
- A mouse-adapted CHAPV variant demonstrated increased virulence and a similar biphasic disease pattern.
Conclusions:
- STAT1-/- mice provide a valuable small-animal model for studying CHAPV infection and Chapare hemorrhagic fever.
- This model recapitulates critical aspects of human CHAPV disease, including biphasic pathology and CNS tropism.
- The developed mouse-adapted CHAPV facilitates further research into arenavirus pathogenesis and therapeutic strategies.
Abstract:
Chapare virus (CHAPV) is an Arenaviridae family member and causative agent of Chapare hemorrhagic fever (CHHF). Endemic to Bolivia, CHAPV was found to be the cause of several outbreaks of CHHF in Bolivia in 2003 and 2019 with high case-fatality rates and instances of human-to-human transmission. The pathogenesis of CHAPV infection is poorly understood, and no vaccines or antivirals are available, in part due to a dearth of available animal models. Mice lacking signal transducer and activator of transcription 1 (STAT1-/-) have been shown to succumb to infection by related arenaviruses, including Machupo virus, and were investigated for their susceptibility to CHAPV infection. Challenge with CHAPV resulted in partial lethality in STAT1-/- mice with a biphasic disease course characterized by initial viral load and pathology in the spleen and liver followed by inflammation and high viral titers in the brain and spinal cord that immediately preceded mortality. Adaptation in the brains of STAT1-/- mice resulted in a fully lethal mouse-adapted CHAPV variant, with a similar biphasic disease course, but virus in tissues was detected more proximal to challenge. The result of this study is a lethal small-animal rodent model for CHAPV that recapitulates many aspects of human CHAPV disease.
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