Abstract
Dengue virus (DENV) infection in the brain causes severe dengue disease with neuropathic complications. In addition to viral effects, immunogenic or pathogenic central nervous system (CNS) inflammation can be induced during DENV infection. By using an immunocompetent outbred ICR (Institute of Cancer Research) mouse model for investigating CNS immunity upon DENV infection, we conducted single-panel immune cell profiling and a multiplex cytokine assay. The ICR mice infected with DENV presented with progressive hunchback posture, limbic seizures, limbic weakness, paralysis, and lethality. When the virions were released, the viral non-structural protein 1 was expressed in the brain in a time-dependent manner. Isolated brain CD45-positive cells revealed a significant population of resident CD14-positive cells, which was considerably decreased 8 days post-infection. We found an unexpected time-kinetic decrease in CD19-positive cells and CD11c/MHC II-positive cells and an increase in NK1.1-positive cells. Further assays showed the time-dependent induction of proinflammatory and NK1.1-associated cytokines in the DENV-infected brains. These results indicate a CNS immune profile of DENV infection and hypothetical CNS immunity in response to DENV infection.
Highlights
Dengue virus (DENV), a mosquito-borne Flavivirus, contains a positive-sense RNA genome that encodes three structural proteins and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5 proteins)
The survival rates were significantly different, with the DENV-infected mice dying after 8 d.p.i., and all mice dying within 11 d.p.i. (p < 0.01) (Figure 1C)
The results reveal the establishment of a reporter DENV-infected murine model with disease progression involving central nervous system (CNS) disorders
Summary
Dengue virus (DENV), a mosquito-borne Flavivirus, contains a positive-sense RNA genome that encodes three structural proteins (pr-M, envelope, and capsid proteins) and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5 proteins). Many studies have shown that DENV can infect various human organs (Shresta et al, 2004; Povoa et al, 2014; Milligan et al, 2015). DENV positive-sense RNA and another viral antigen, NS1, can be detected in human spleen, lung, liver, and CNS tissues (Povoa et al, 2014). Upon DENV infection, AG129 mice show a widespread distribution of infectious viruses in multiple organs, including their livers, spleens, and large intestines, as well as their brains and spinal cords (Shresta et al, 2004; Milligan et al, 2015). Lethal dengue disease is characterized by the robust induction of cytokines and chemokines in mouse serum, such as interleukin (IL)-6, IL-10, and interferon (IFN)-γ, showing a high correlation with infectious disease progression (Sarathy et al, 2015)
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