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Viral Tracing of Genetically Defined Neural Circuitry
Published on: October 17, 2012
Visualization of a neurotropic flavivirus infection in mouse reveals unique viscerotropism controlled by host type I
Xiao-Feng Li1, Xiao-Dan Li2, Cheng-Lin Deng2
1Department of Virology, State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China.
Abstract:
Flavivirus includes a large group of human pathogens with medical importance. Especially, neurotropic flaviviruses capable of invading central and peripheral nervous system, e.g. Japanese encephalitis virus (JEV) and Zika virus (ZIKV), are highly pathogenic to human and constitute major global health problems. However, the dynamic dissemination and pathogenesis of neurotropic flavivirus infections remain largely unknown. Here, using JEV as a model, we rationally designed and constructed a recombinant reporter virus that stably expressed Renilla luciferase (Rluc). The resulting JEV reporter virus (named Rluc-JEV) and parental JEV exhibited similar replication and infection characteristics, and the magnitude of Rluc activity correlated well with progeny viral production in vitro and in vivo. By using in vivo bioluminescence imaging (BLI) technology, we dissected the replication and dissemination dynamics of JEV infection in mice upon different inoculation routes. Interestingly, besides replicating in mouse brain, Rluc-JEV predominantly invaded the abdominal organs in mice with typical viscerotropism. Further tests in mice deficient in type I interferon (IFN) receptors demonstrated robust and prolonged viral replication in the intestine, spleen, liver, kidney and other abdominal organs. Combined with histopathological and immunohistochemical results, the host type I IFN signaling was evidenced as the major barrier to the viscerotropism and pathogenicity of this neurotropic flavivirus. Additionally, the Rluc-JEV platform was readily adapted for efficacy assay of known antiviral compounds and a live JE vaccine. Collectively, our study revealed abdominal organs as important targets of JEV infection in mice and profiled the unique viscerotropism trait controlled by the host type I IFN signaling. This in vivo visualization technology described here provides a powerful tool for testing antiviral agents and vaccine candidates for flaviviral infection.
Insights
Japanese encephalitis virus (JEV) can infect abdominal organs, not just the brain. Host type I interferon signaling restricts this viscerotropism, offering new targets for antiviral therapies and vaccines.
Area of Science:
- Virology
- Immunology
- Infectious Diseases
Background:
- Neurotropic flaviviruses like Japanese encephalitis virus (JEV) pose significant global health threats.
- The dissemination and pathogenesis of these viruses, particularly their spread beyond the nervous system, are not fully understood.
Purpose of the Study:
- To develop a reporter virus for tracking JEV dynamics in vivo.
- To investigate the dissemination and pathogenesis of JEV infection using a novel reporter system.
- To identify host factors controlling JEV viscerotropism.
Main Methods:
- Construction of a recombinant Renilla luciferase (Rluc)-expressing JEV reporter virus (Rluc-JEV).
- In vivo bioluminescence imaging (BLI) to monitor viral replication and dissemination in mice.
- Analysis of viral loads and host responses in wild-type and type I interferon receptor-deficient mice.
- Histopathological and immunohistochemical analyses.
Main Results:
- Rluc-JEV accurately reflects parental JEV replication and viral production.
- JEV exhibits significant tropism for abdominal organs (viscerotropism) in mice, beyond neuroinvasion.
- Type I interferon signaling acts as a critical barrier limiting JEV replication in abdominal organs.
- The Rluc-JEV platform demonstrated utility in evaluating antiviral compounds and a JE vaccine.
Conclusions:
- Abdominal organs are significant targets for JEV infection, revealing a previously underappreciated viscerotropism.
- Host type I interferon signaling plays a crucial role in controlling JEV viscerotropism and pathogenicity.
- The developed Rluc-JEV reporter system and BLI technology offer a powerful tool for flavivirus research, antiviral drug screening, and vaccine development.
