Precise localization and dynamic distribution of Japanese encephalitis virus in the rain nuclei of infected mice
Open Access
- 21 June 2021
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLoS Neglected Tropical Diseases
- Vol. 15 (6), e0008442
- https://doi.org/10.1371/journal.pntd.0008442
Abstract
Japanese encephalitis virus (JEV) is a pathogen that causes severe vector-borne zoonotic diseases, thereby posing a serious threat to human health. Although JEV is potentially neurotropic, its pathogenesis and distribution in the host have not been fully elucidated. In this study, an infected mouse model was established using a highly virulent P3 strain of JEV. Immunohistochemistry and in situ hybridization, combined with anatomical imaging of the mouse brain, were used to dynamically localize the virus and construct three-dimensional (3D) images. Consequently, onset of mild clinical signs occurred in some mice at 3.5 d post JEV infection, while most mice displayed typical neurological signs at 6 d post-infection (dpi). Moreover, brain pathology revealed typical changes associated with non-suppurative encephalitis, which lasted up to 8 d. The earliest detection of viral antigen was achieved at 3 dpi in the thalamus and medulla oblongata. At 6 dpi, the positive viral antigen signals were mainly distributed in the cerebral cortex, olfactory area, basal ganglia, thalamus, and brainstem regions in mice. At 8 dpi, the antigen signals gradually decreased, and the localization of JEV tended to concentrate in the cerebrum and thalamus, while no viral antigen was detected in the brain at 21 dpi. In this model, the viral antigen was first expressed in the reticular thalamic nucleus (Rt), and the virus content is relatively stable. The expression of the viral antigen in the hippocampal CA2 region, the anterior olfactory nucleus, and the deep mesencephalic nucleus was high and persistent. The 3D images showed that viral signals were mostly concentrated in the parietal cortex, occipital lobe, and hippocampus, near the mid-sagittal plane. In the early stages of infection in mice, a large number of viral antigens were detected in denatured and necrotic neurons, suggesting that JEV directly causes neuronal damage. From the time of its entry, JEV is widely distributed in the central nervous system thereby causing extensive damage. There are many theories regarding the mechanism of entry of the Japanese encephalitis virus (JEV) into the nervous system. The inflammation cascade effect, resulting from the virus entering the central nervous system (CNS), is a major cause of brain injury in JEV patients. In this study, we found that the earliest point at which viral antigen was detected in the brain tissues following peripheral infection of JEV was at 3d. The virus was located in the nerve nuclei of the thalamus and medulla oblongata and, subsequently, viral antigens were found in the anterior olfactory nucleus. At 4 dpi, the virus was extensively distributed in the brain tissue, and at 6 d -8 d the viral antigen was widely distributed and highly concentrated. The viral concentration detected in the ventromedial thalamic nucleus (VM), deep mesencephalic nucleus (DpMe), and motor trigeminal nucleus (Mo5) remained high throughout the experiment. The hypertrophic nerve nuclei of JEV include the early anterior olfactory (AO) nucleus and the late hippocampal CA2 region. In the early stages of viral infection (6 dpi), the changes in viral antigen concentration and mortality rate were consistent. It was hypothesized that this stage represents the activation of viral proliferation and brain inflammation.Funding Information
- National Key Research and Development Program of China (2016YFD0500407)
- National Key Research and Development Program of China (2016YFD0500407)
- National Natural Sciences Foundation of China (32030107)
- National Natural Sciences Foundation of China (32030107)
This publication has 33 references indexed in Scilit:
- The contribution of rodent models to the pathological assessment of flaviviral infections of the central nervous systemArchiv für die gesamte Virusforschung, 2012
- Monoclonal Antibodies Against NS3 and NS5 Proteins of Japanese Encephalitis VirusHybridoma, 2012
- Pathological basal ganglia activity in movement disordersNeuroscience, 2011
- Estimated global incidence of Japanese encephalitis:Bulletin of the World Health Organization, 2011
- RIG-I Mediates Innate Immune Response in Mouse Neurons Following Japanese Encephalitis Virus InfectionPLOS ONE, 2011
- Microbes' roadmap to neuronsNature Reviews Neuroscience, 2011
- Japanese encephalitis virus co-opts the ER-stress response protein GRP78 for viral infectivityVirology Journal, 2011
- Axonal transport mediates West Nile virus entry into the central nervous system and induces acute flaccid paralysisProceedings of the National Academy of Sciences of the United States of America, 2007
- Langerhans Cells Migrate to Local Lymph Nodes Following Cutaneous Infection with an ArbovirusJournal of Investigative Dermatology, 2000
- Protection of adult but not newborn mice against lethal intracerebral challenge with Japanese encephalitis virus by adoptively transferred virus-specific cytotoxic T lymphocytes: requirement for L3T4+ T cellsJournal of General Virology, 1996