Flaviviruses are positive-sense single-stranded, vector-borne RNA viruses that can infect a broad range of hosts. It can spread unexpectedly in human populations and cause a spectrum of potentially severe diverse range of diseases including hepatitis, vascular shock syndrome, encephalitis, acute flaccid paralysis, congenital abnormalities, and fetal death. Flaviviruses are transmitted primarily by arthropods. Most areas of the globe are endemic for at least one flavivirus, putting billions of the population at risk for infections. Flaviviruses are now globally distributed and infect up to 400 million people annually. The Flaviviridae family of RNA viruses includes several human disease-causing pathogens that are largely increasing in prevalence due to continuous climate change, rising population sizes, and improved global travel. The majority of mosquito-infecting flaviviruses have been associated with members of the Culicinae subfamily, mainly from the Culex and Aedes genera. Though the potential for the viruses to sustain epidemic transmission among humans is poorly understood. Symptoms of flavivirus infection range from mild fever, malaise to fatal encephalitis and haemorrhagic fever. The genus of flavivirus consists of more than 70 members. Many of these viruses, such as the West Nile virus, dengue virus, tick-borne encephalitis virus, Japanese encephalitis virus, and yellow fever virus, cause serious human diseases, such as encephalitis and fatal hemorrhagic fever. Infection by mosquito-borne flaviviruses is becoming prevalent worldwide. Research found that inflammatory chemokine osteopontin (OPN) is capable of loosening the blood‐brain barrier in mice and promote WNV nerve invasive infection.
Mechanisms by Which Flaviviruses Can Penetrate the Blood‐Brain Barrier
Flaviviruses possess the capability to penetrate the blood‐brain barrier through various mechanisms that lead to neuropathy. Remarkably, JEV16 and DENV17 have been found to cross the blood‐brain barrier and cause encephalitis. Perivascular pericytes infected with flaviviruses recruit inflammatory cytokines and open TH17/TH9‐controlled gates to increase the permeability of the blood‐brain barrier. However, with the enormous prevalence and impact on the human population, minimal flaviviruses with approved human vaccines are applicable to date: yellow fever (YF), tick-borne encephalitis virus (TBEV), Japanese encephalitis virus (JEV), and dengue virus (DENV).
Consequences of Inflammation
Subsequent breaches and inflammation in the blood‐brain barrier play an essential role in JEV invasion of the central nervous system (CNS). Microvascular pericytes infection in the brain can amplify or induce neuroinflammation caused by JEV infection. Scientists have found that the inflammatory chemokine osteopontin (OPN) can loosen the blood‐brain barrier in mice and promote WNV nerve invasion. Study reveals that interferon (IFN) signaling regulates the permeability of the blood‐brain barrier after WNV infection. By reducing the steady‐state level of tyrosine phosphorylation and antagonizing the immune response induced by IFN, WNV affects the activation of the JAK‐STAT pathway. It is speculated that inflammation may assist the entry of flaviviruses and allow them to infect brain tissues. Higher loads of JEV have the potential to subvert host cell apoptosis by deactivating proapoptotic proteins. In addition to causing inflammation, apoptosis damages the barrier cells to increase the effects of inflammation, magnifying the resulting neuropathies. A number of studies found that the virus can activate the endothelial cells and affect the structure and function of the blood‐brain barrier, promoting immune cell migration to benefit the virus nervous system target cells infected by flaviviruses.
Cells of Nervous System Infected by Flaviviruses
Neural Progenitor Cells: JEV can suppress the cycling of neural progenitor cells (NPCs), preventing proliferation. Regarding the differentiation of neural stem/progenitor cells (NSPCs), neuronal and astrocyte differentiation both appear as severely affected.
Glial Cells: White matter astrocytes are found as the key responders to viral infections. The ability of microglial cells to spread and increase inflammatory effects supports the infection of other cells.
Cortical and Neural Cells: Flaviviruses infects human nerve cells, causing neuronal damage. Research on the target cells in the nervous system infected by flaviviruses help to understand the causes of neurological symptoms.
Targets for Drug Discovery
Flaviviruses are a significant cause of infectious diseases in humans. Despite the existence of licensed vaccines, yellow fever, Japanese encephalitis, and tick-borne encephalitis claim thousands of victims every year across their vast endemic areas. The envelope glycoprotein, NS3 helicase, NS3 protease, NS5 methyltransferase, and NS5 RNA-dependent RNA polymerase as potential drug targets, and special attention is given to viral protease. Precursor herpesvirus drugs, antiretroviral drugs that target reverse transcriptase and protease, influenza virus directed compounds and more recent direct antiviral agents (DAA) applied in the treatment of hepatitis C virus (HCV).
Flaviviruses can enter nerve cells through diverse routes, such as through high‐affinity interactions with cell membrane receptors. Cells are susceptible to flavivirus infection following the interactions. Prophylactic vaccination has become an intense area of research used to protect against flavivirus infection in the last several decades due to the inherent nature of the family of the viruses to cause explosive outbreaks. Understanding the virus lifecycle at the molecular level can eventually lead to novel and potent treatment strategies.