Abstract
Patients with dengue virus (DENV) infection may also present acute viral encephalitis through an unknown mechanism. Here, we report that encephalitic DENV-infected mice exhibited progressive hunchback posture, limbic seizures, limbic weakness, paralysis, and lethality 7 days post-infection. These symptoms were accompanied by CNS inflammation, neurotoxicity, and blood-brain barrier destruction. Microglial cells surrounding the blood vessels and injured hippocampus regions were activated by DENV infection. Pharmacologically depleting microglia unexpectedly increased viral replication, neuropathy, and mortality in DENV-infected mice. In microglia-depleted mice, the DENV infection-mediated expression of antiviral cytokines and the infiltration of CD8-positive cytotoxic T lymphocytes (CTLs) was abolished. DENV infection prompted the antigen-presenting cell-like differentiation of microglia, which in turn stimulated CTL proliferation and activation. These results suggest that microglial cells play a key role in facilitating antiviral immune responses against DENV infection and acute viral encephalitis.
Highlights
The neuropathogenesis of dengue virus (DENV) infection requires further investigation with regards to the neurological manifestations experienced by severe dengue patients
The neurological complications associated with severe dengue disease show CNS involvement and neurological dysfunction, the neuropathogenesis of dengue encephalitis is still unclear[11]
There are several emerging and unresolved questions still open for investigation, including the length of behavioral changes, the neuroinvasive capacity of DENV, the neurovirulence of different DENV serotypes, the routes of infection in the brain, the cells in the brain targeted by DENV and their possible roles in infection, immune defense in the brain, and the pathogenic role of CNS inflammation related to BBB destruction and intracerebral hemorrhaging
Summary
The neuropathogenesis of DENV infection requires further investigation with regards to the neurological manifestations experienced by severe dengue patients. These may be the result of direct neurotoxicity by DENV, hepatic failure, or the involvement of hemorrhagic complications, including thrombocytopenia, intracranial bleeding, prolonged shock, and hyponatremia. A neuroadapted strain of DENV inoculated intraperitoneally in postnatal mice induces fatal encephalitis accompanied by limb paralysis and postural instability concomitant with efficient viral replication in the brain that likely occurs as a result of general and localized plasma leakage through the BBB14. This study investigated the role of DENV-infected microglia in vivo, with regards to CNS inflammation, neurotoxicity, encephalitis, and antiviral immune defense
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