T Cells in Tick-Borne Flavivirus Encephalitis: A Review of Current Paradigms in Protection and Disease Pathology

Abstract

The family Flaviviridae is comprised of a diverse group of arthropod-borne viruses that are the etiological agents of globally relevant diseases in humans. Among these, infection with several of these flaviviruses—including West Nile virus (WNV), Zika virus (ZIKV), Japanese encephalitis virus (JEV), tick-borne encephalitis virus (TBEV), and Powassan virus (POWV)—can result in neuroinvasive disease presenting as meningitis or encephalitis. Factors contributing to the development and resolution of tick-borne flavivirus (TBEV, POWV) infection and neuropathology remain unclear, though many recently undertaken studies have described the virus–host interactions underlying encephalitic disease. With access to neural tissues despite the selectively permeable blood–brain barrier, T cells have emerged as one notable contributor to neuroinflammation. The goal of this review is to summarize the recent advances in tick-borne flavivirus immunology—particularly with respect to T cells—as it pertains to the development of encephalitis. We found that although T cell responses are rarely evaluated in a clinical setting, they are integral in conjunction with antibody responses to restricting the entry of TBFV into the CNS. The extent and means by which they can drive immune pathology, however, merits further study. Understanding the role of the T cell compartment in tick-borne flavivirus encephalitis is instrumental for improving vaccine safety and efficacy, and has implications for treatments and interventions for human disease.

Tick-Borne Encephalitis Virus: A Comprehensive Review of Transmission, Pathogenesis, Epidemiology, Clinical Manifestations, Diagnosis, and Prevention

“…By diffusion from capillary endothelial cells through the highly permeable blood-brain barrier [108] Studies performed on neurons and astrocytes differentiated from human neural progenitor cells (hNPCs) have shown that this cell type is permissive of TBEV infection [113].…”

“…During viremia, tick-borne encephalitis virus passes the blood–brain barrier (BBB) and thereby enters the central nervous system (CNS) [ 108 ]. Neurons are the primary targets of TBEV infection in the CNS, but it is important to note that the exact mode of entry into the CNS and the cell receptors are still not fully understood [ 109 , 110 ].…”

Tick-borne zoonotic flaviviruses and Borrelia infections in wildlife hosts: What have field studies contributed?

“…Recent reviews on tick-borne Borrelia spp. and TBFV have focused on getting information on the biology of infection in vertebrate hosts [ 13 , 14 ], reporting prevalence and clinical cases in human [ 15 , 16 ] and discussing diagnostic methodologies [ 17 , 18 ], the role of non-vector transmissions for TBFV [ 19 , 20 ], or on the importance of modelling TBP regarding climate change [ 21 , 22 ]. Some reviews have focused on wildlife hosts but only at a national or continental scale [ 23 , 24 ], or on reservoirs associated with flaviviruses in general, with little focus on TBFV [ 25 ].…”

Tick-borne zoonotic flaviviruses andBorreliainfections in wildlife hosts: what have field studies contributed?

“…Recent reviews on tick-borne Borrelia spp. and TBFV have focused on getting information on the biology of infection in vertebrate hosts[14,15], reporting prevalence and clinical cases in human[16,17] and discussing diagnostic methodologies[18,19], the role of non-vector transmissions for TBFV[20,21], or on the importance of modelling TBP regarding climate change[22,23]. Some reviews have focused on wildlife hosts but only at a national or continental scale[24,25], or on reservoirs associated with flaviviruses in general, with little focus on TBFV[26].…”