Laboratory of Arbovirology
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Current research projects
Neurovascular unit cells interactions leading to the blood-brain barrier breakdown during tickborne encephalitis (Czech Science Foundation, 2020-2023, P.I.: Martin Palus)
Tick-borne encephalitis, major public health threat among zoonotic arbovirosis. Despite the medical importance of this disease, there is no specific treatment and crucial steps in pathogenesis are poorly characterized. The infection results in neurodegeneration by a mechanism that is not yet fully understood, but it is known that the structural and functional integrity of the blood-brain barrier (BBB) is compromised and that these alterations have impacts on the development of TBE. We are going to challenge the hypothesis leading to identification of key features of a potential mechanism of disruption of endothelial barrier integrity during the course of TBE virus infection through the activation of neighboring cells. No detailed study of disease in the CNS can be complete without consideration of all participating cell types (astrocytes, pericytes, microglia and endothelial cells) and their interactions within the microenvironment of human BBB. It is hoped that this proposal will instill a new appreciation for the human neurovascular cell interactions during TBE development.
We are going to study TBEV interactions with human neurovascular unit cells, reveal the mechanisms of their injury, describe the interaction of the infected cells with other key cell types in the CNS and identify the molecular aspects leading to blood-brain barrier failure
Molecular mechanisms of tick-borne encephalitis pathogenesis (Czech Science Foundation, 2020-2023, P.I.: Daniel Růžek)
Tick-borne encephalitis (TBE) represents one of the most serious neuro-infections in Europe and Northeastern Asia. Despite the medical importance of this disease, the biology of the virus as well as the mechanisms of pathogenesis of TBE remain poorly understood. Here we propose a new project to study several aspects of TBE virus biology and to identify mechanisms of viral neuroinvasion. Moreover, we will address key questions related to the role of immunopathology in the development of TBE. Our preliminary data strongly indicate that the immune response is an important cause of neuron death. This is in contrast to the prevailing hypothesis that neuronal loss is mediated solely by virus infection.
The project aims at identifying viral virulence determinants, mechanism(s) by which the virus invades host brain and how the infection triggers exuberant immune responses.
Differences in clinical course of tick-borne encephalitis in host, and their genetic determination.
Tick-borne encephalitis (TBE), a disease caused by tick-borne encephalitis virus (TBEV), represents a serious viral neuroinfection of humans. Despite the medical importance of this disease, some crucial steps in the development of encephalitis remain poorly understood. In humans, TBEV may produce a variety of clinical symptoms, from an asymptomatic disease to a fever and acute or chronic progressive encephalitis. This is influenced by a variety of factors, e.g. inoculation dose and virulence of the virus, age and immune status of the host, but also, as our preliminary results strongly suggest, by susceptibility based on host genetic background. Here, we propose a research project to study differences in clinical course of tick-borne encephalitis, and its genetical determination. As a model for TBE, recombinant congenic mouse strains will be used, since these mice develop TBE of various severity, and this correlates with the situation in humans. Results of this project should improve our understanding of the genetic basis of seriousness of this important infection.
Mechanisms of neuronal injury during tick-borne encephalitis virus infection of the CNS
The mechanisms of TBEV-induced injury to the central nervous system (CNS) are unclear. To address this issue we study interactions of TBEV with primary human neurons, mechanisms of their injury and antiviral defence, as well as the interaction of the infected neurons with other key cells in the CNS (astrocytes, pericytes, microglia and brain microvascular epithelial cells). We propose that the innate immune response is an important cause of neuron death during the acute infection.This is in contrast to the prevailing hypothesis that neuron loss is mediated solely by virus. The results of this project should provide new crucial data about the neuropathogenesis of TBE.
