Abstract
Oropouche virus (OROV) is an emerging arbovirus in South and Central Americas with high spreading potential. OROV infection has been associated with neurological complications and OROV genomic RNA has been detected in cerebrospinal fluid from patients, suggesting its neuroinvasive potential. Motivated by these findings, neurotropism and neuropathogenesis of OROV have been investigated in vivo in murine models, which do not fully recapitulate the complexity of the human brain. Here we have used slice cultures from adult human brains to investigate whether OROV is capable of infecting mature human neural cells in a context of preserved neural connections and brain cytoarchitecture. Our results demonstrate that human neural cells can be infected ex vivo by OROV and support the production of infectious viral particles. Moreover, OROV infection led to the release of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α) and diminished cell viability 48 h post-infection, indicating that OROV triggers an inflammatory response and tissue damage. Although OROV-positive neurons were observed, microglia were the most abundant central nervous system (CNS) cell type infected by OROV, suggesting that they play an important role in the response to CNS infection by OROV in the adult human brain. Importantly, we found no OROV-infected astrocytes. To the best of our knowledge, this is the first direct demonstration of OROV infection in human brain cells. Combined with previous data from murine models and case reports of OROV genome detection in cerebrospinal fluid from patients, our data shed light on OROV neuropathogenesis and help raising awareness about acute and possibly chronic consequences of OROV infection in the human brain.
Highlights
Neurotropic viruses can potentially cause central nervous system (CNS) diseases (Abdullahi et al, 2020)
We have observed no major constraints in cell viability and tissue morphology/cytoarchitecture in these human brain-derived slice cultures that could impose a significant limitation to the use of this model for studying virus neuroinfection (Mendes et al, 2018; Fernandes et al, 2019)
A significant advantage of this model is to preserve the original cellular population and connections found in the adult human brain, as we have previously shown the presence of neurons, microglia and astrocytes by light microscopy in re-sectioned slices submitted to DAB-Nickel immunostaining (Fernandes et al, 2019)
Summary
Neurotropic viruses can potentially cause central nervous system (CNS) diseases (Abdullahi et al, 2020). The mechanisms that lead to neuroinvasion are not completely known for all neurotropic viruses, but some infection pathways include breach of the blood-brain barrier, Trojan horse effect, crossing of the choroid plexus, endothelial transcytosis, access by peripheral nerves and/or olfactory neurons (Koyuncu et al, 2013). About 20–50% of diagnosed encephalitis are attributed to viruses, which underscores the importance of understanding virus infection in CNS (Tyler, 2018). Arthropod-borne viruses, called arboviruses, from diverse viral families cause important human diseases around the world, and several of them are able to reach the CNS and cause neurological complications (Wasay et al, 2015). West Nile virus (family Flaviviridae), another important neurotropic arbovirus, may lead to significant cortical thinning in infected individuals, resulting in long-term neurological damage (Sejvar, 2007; Murray et al, 2018)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
