The Involvement of Neuroinflammation in Dengue Viral Disease: Importance of Innate and Adaptive Immunity

Abstract

Neuroinflammation (inflammation in brain) has been known to play an important role in the development of dengue virus disease. Recently, studies from both clinical and experimental models suggest the involvement of neuroinflammation in dengue viral disease. Studies in clinical setup demonstrated that, microglial cells are actively involved in the patients having dengue virus infection, showing involvement of innate immune response in neuroinflammation. It was further proved that, clinical isolates of dengue-2 virus were able to initiate the pathologic response when injected in the mice brain. Natural killer cells were also found to play a crucial role to activate adaptive immune response. Notably, CXCL10/IFN-inducible protein 10 and CXCR3 are involved in dengue virus-mediated pathogenesis and play an important role in the development of dengue virus-mediated paralysis. In a latest report, it was seen that intracranial injection of dengue virus increases the CD8<sup>+</sup> T-cell infiltration in brain, showing an important mechanism of neuroinflammation during the dengue virus infection. A similar study has described that, when DENV-3 is injected into the mice, it enhances the infiltration of CD8<sup>+</sup> and CD4<sup>+</sup> T cells as well as neutrophils. Cells immune-reactive against NS3 antigen were found throughout the brain. In conclusion, we focus on the various molecular mechanisms which contribute to the basic understanding about the role of neuroinflammation in dengue fever. These mechanisms will help in better understanding dengue pathophysiology and thus help in the development of possible therapeutics.

Incidence of dementia after dengue fever: Results of a longitudinal population‐based study

“…24 Dengue virus may lead to neuroinflammation by infecting the brain and having either a directly neurotoxic effect or an indirectly neurotoxic effect via systemic inflammation. 25,26 Dengue virus is not generally considered a neurotropic pathogen, but some studies have found dengue virus in the CNS. 27 Clinical evidence indicates that the dengue virus can enter CNS via the hematogenous and axonal transport route 27,28 and infect different neurovascular unit cells, including neuron, microglial, and endothelial cells.…”

“…28 Microglial cells, such as the immune cells of the CNS, 29 are activated in dengue virus infection, showing the association between dengue virus infection and neuroinflammation. 26 Studies of animal models demonstrated the loss of hippocampus neurons in dengue virus infection, suggesting its long-term effect on learning and memory. 30 Neurocognitive consequences such as memory impairment have been reported in patients with dengue infection.…”

“…Previous studies found that infectious diseases, such as hepatitis C, Helicobacter pylori infection, cytomegalovirus, chronic periodontitis, or even sepsis, were associated with an increased risk of dementia via inflammatory changes in the brain 24 . Dengue virus may lead to neuroinflammation by infecting the brain and having either a directly neurotoxic effect or an indirectly neurotoxic effect via systemic inflammation 25,26 . Dengue virus is not generally considered a neurotropic pathogen, but some studies have found dengue virus in the CNS 27 .…”

“…Clinical evidence indicates that the dengue virus can enter CNS via the hematogenous and axonal transport route 27,28 and infect different neurovascular unit cells, including neuron, microglial, and endothelial cells 28 . Microglial cells, such as the immune cells of the CNS, 29 are activated in dengue virus infection, showing the association between dengue virus infection and neuroinflammation 26 . Studies of animal models demonstrated the loss of hippocampus neurons in dengue virus infection, suggesting its long‐term effect on learning and memory 30 .…”

Neurological Damage by Coronaviruses: A Catastrophe in the Queue!

“…The role of exosomes and other extracellular vesicles in Dengue viral hemorrhagic fever has also been discussed to highlight the importance of exosomal secretion in cytokine storm phenomenon (59). Even viral proteins such as HIV-1 Tat, Nef, and Dengue NS1 circulate in the bloodstream and trigger the generation and transportation of cytokines to multiple organs, including the CNS (73)(74)(75)(76)(77). Ultimately, all these influxes of peripheral inflammatory molecules inside the CNS activate the brain resident macrophages, i.e., microglia, which becomes hyper-activated and starts producing its own set of inflammatory molecules and causes neuroinflammation.…”