Dengue Virus Infection of Blood–Brain Barrier Cells: Consequences of Severe Disease

Abstract

More than 500 million people worldwide are infected each year by any of the four-dengue virus (DENV) serotypes. The clinical spectrum caused during these infections is wide and some patients may develop neurological alterations during or after the infection, which could be explained by the cryptic neurotropic and neurovirulent features of flaviviruses like DENV. Using in vivo and in vitro models, researchers have demonstrated that DENV can affect the cells from the blood–brain barrier (BBB) in several ways, which could result in brain tissue damage, neuronal loss, glial activation, tissue inflammation and hemorrhages. The latter suggests that BBB may be compromised during infection; however, it is not clear whether the damage is due to the infection per se or to the local and/or systemic inflammatory response established or activated by the BBB cells. Similarly, the kinetics and cascade of events that trigger tissue damage, and the cells that initiate it, are unknown. This review presents evidence of the BBB cell infection with DENV and the response established toward it by these cells; it also describes the consequences of this response on the nervous tissue, compares these evidence with the one reported with neurotropic viruses of the Flaviviridae family, and shows the complexity and unpredictability of dengue and the neurological alterations induced by it. Clinical evidence and in vitro and in vivo models suggest that this virus uses the bloodstream to enter nerve tissue where it infects the different cells of the neurovascular unit. Each of the cell populations respond individually and collectively and control infection and inflammation, in other cases this response exacerbates the damage leaving irreversible sequelae or causing death. This information will allow us to understand more about the complex disease known as dengue, and its impact on a specialized and delicate tissue like is the nervous tissue.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and glial cells: Insights and perspectives

“…Another possible mechanism of CNS infection by SARS-CoV-2 is through infection of vascular ECs, which have already been reported to be infected by SARS-CoV-2 ( Varga et al., 2020 ). In addition, other neurovirulent viruses, such as some strains of Dengue Fever virus, are also capable of reaching the CNS by infecting ECs to cross the BBB ( Calderon-Pelaez et al., 2019 ). Apart from direct EC infection, the important systemic inflammation observed in COVID-19 patients can also induce BBB disruption ( Sankowski et al., 2015 ), allowing potential entry of infected leukocytes into the CNS.…”

Topology, Antiviral Functional Residues and Mechanism of IFITM1

“…DENV, like ZIKV, is a member of the Flavivirus genus. More than 500 million people worldwide are infected each year by any of the four-DENV serotypes [23]. To further verify the importance of the KRRK basic residues of IFITM1 against viruses, IFITM1 and KRRK mutants were used to detect their restriction on the DENV-2 TSV01 strain in Vero cells.…”

Repurposing the Antiemetic Metoclopramide as an Antiviral Against Dengue Virus Infection in Neuronal Cells

“…DENV can be identified in the cerebrospinal fluid and the brain tissue of encephalitis patients ( Verma et al, 2014 ). It has been suggested that DENV can enter neuronal systems through membrane receptors and contribute to neurological manifestations, including encephalitis, encephalopathy, and dengue-associated neuromuscular complications ( Calderon-Pelaez et al, 2019 ). Appropriate medical interventions are needed to prevent neurological complications and death.…”