West Nile Virus Neuroinfection in Humans: Peripheral Biomarkers of Neuroinflammation and Neuronal Damage

Abstract

Among emerging arthropod-borne viruses (arbovirus), West Nile virus (WNV) is a flavivirus that can be associated with severe neuroinvasive infections in humans. In 2018, the European WNV epidemic resulted in over 2000 cases, representing the most important arboviral epidemic in the European continent. Characterization of inflammation and neuronal biomarkers released during WNV infection, especially in the context of neuronal impairments, could provide insight into the development of predictive tools that could be beneficial for patient outcomes. We first analyzed the inflammatory signature in the serum of WNV-infected mice and found increased concentrations of several inflammatory cytokines. We next analyzed serum and cerebrospinal-fluid (CSF) samples from a cohort of patients infected by WNV between 2018 and 2019 in Hungary to quantify a large panel of inflammatory cytokines and neurological factors. We found higher levels of inflammatory cytokines (e.g., IL4, IL6, and IL10) and neuronal factors (e.g., BDNF, GFAP, MIF, TDP-43) in the sera of WNV-infected patients with neuroinvasive disease. Furthermore, the serum inflammatory profile of these patients persisted for several weeks after initial infection, potentially leading to long-term sequelae and having a deleterious effect on brain neurovasculature. This work suggests that early signs of increased serum concentrations of inflammatory cytokines and neuronal factors could be a signature underlying the development of severe neurological impairments. Biomarkers could play an important role in patient monitoring to improve care and prevent undesirable outcomes.

Powassan Virus Induces Structural Changes in Human Neuronal Cells In Vitro and Murine Neurons In Vivo

“…Infection with TBEV in neuronal cell lines, as well as primary astrocytes, has confirmed that an inflammatory response is elicited [ 14 , 17 ]. These inflammatory responses have also been described in human cases for both WNV and POWV, as well as in animal models [ 8 , 11 , 12 , 18 , 19 , 20 ].…”

A Journey to the Central Nervous System: Routes of Flaviviral Neuroinvasion in Human Disease

“…In general, elevated levels of proinflammatory cytokines and chemokines in the serum and CSF is associated with poor disease outcome, but it is not known whether this is an indicator of severe disease or actually contributory to pathogenesis. Acute-phase TBE patients have shown elevated MMP-9 in the serum and CSF [ 54 , 55 ], whilst patients with WNV infection exhibited elevated serum/plasma levels of a number of inflammatory cytokines [ 56 , 57 ] including IL-1β, TNF-α and IFN-γ [ 57 ] and MMP-9 [ 43 ] all of which have been shown to compromise the BBB [ 38 , 43 , 58 , 59 , 60 ]. Indeed, addition of sera from WNV neurological disease patients to an in vitro BBB model led to a slight increase in barrier permeability [ 56 ].…”

“…Acute-phase TBE patients have shown elevated MMP-9 in the serum and CSF [ 54 , 55 ], whilst patients with WNV infection exhibited elevated serum/plasma levels of a number of inflammatory cytokines [ 56 , 57 ] including IL-1β, TNF-α and IFN-γ [ 57 ] and MMP-9 [ 43 ] all of which have been shown to compromise the BBB [ 38 , 43 , 58 , 59 , 60 ]. Indeed, addition of sera from WNV neurological disease patients to an in vitro BBB model led to a slight increase in barrier permeability [ 56 ]. The high levels of neuroinflammatory biomarkers in these sera and the neurological clinical presentations of these patients indicates an advanced stage of neuroinvasive disease.…”

The relationship between chronic immune response and neurodegenerative damage in long COVID-19

“…It is also known that patients infected with human orthopneumovirus and presenting neurological symptoms such as encephalitis and encephalopathies, have elevated levels of the proinflammatory cytokines IL-6, IL-8, CCL2, and CCL4 in CSF samples (136,137). West Nile virus is also known to cause a neuroinvasive disease manifesting meningitis, meningoencephalitis, encephalitis, or acute flaccid paralysis, commonly associated with diarrhea/vomiting, weakness, impaired vision, confusion, or drowsiness, and shows elevated levels of proinflammatory cytokines IL4, IL6, and IL10 in serum samples (138). Finally, Zika virus can infect the CNS and induce microcephaly in fetuses and rare but serious neurological diseases in adults, which are associated with excessive production of IFNa, IFN-b, IL-6, and TNF-a (139).…”