Abstract
The environment of the central nervous system (CNS) represents a double-edged sword in the context of viral infections. On the one hand, the infectious route for viral pathogens is restricted via neuroprotective barriers; on the other hand, viruses benefit from the immunologically quiescent neural environment after CNS entry. Both the herpes simplex virus (HSV) and the rabies virus (RABV) bypass the neuroprotective blood–brain barrier (BBB) and successfully enter the CNS parenchyma via nerve endings. Despite the differences in the molecular nature of both viruses, each virus uses retrograde transport along peripheral nerves to reach the human CNS. Once inside the CNS parenchyma, HSV infection results in severe acute inflammation, necrosis, and hemorrhaging, while RABV preserves the intact neuronal network by inhibiting apoptosis and limiting inflammation. During RABV neuroinvasion, surveilling glial cells fail to generate a sufficient type I interferon (IFN) response, enabling RABV to replicate undetected, ultimately leading to its fatal outcome. To date, we do not fully understand the molecular mechanisms underlying the activation or suppression of the host inflammatory responses of surveilling glial cells, which present important pathways shaping viral pathogenesis and clinical outcome in viral encephalitis. Here, we compare the innate immune responses of glial cells in RABV- and HSV-infected CNS, highlighting different viral strategies of neuroprotection or Neuroinflamm. in the context of viral encephalitis.
Highlights
Inside the central nervous system (CNS), the neuronal network is protected from pathogens via resident glial cells, which can be divided into oligodendrocytes, astrocytes, and microglia
Deciphering the requirements for a strict neuron-specific tropism or broader host cell multitropism in the nervous system and discovering cell-specific responses restricting viral replication is of utmost importance to understand viral pathogenesis and antiviral host mechanisms
Detailed research is still needed on that point, especially on why herpes simplex virus (HSV)-1 maintains the devastating potential to reach the CNS in rare cases, but otherwise resides latently in peripheral ganglia [172]. It is not yet clear whether HSV-1 reaches the CNS directly after primary infection, which leads to encephalitis, or whether this happens after reactivation of the virus in latent infected tissue [44]
Summary
In contrast to other tissues, the micromilieu of the central nervous system (CNS) tightly controls brain immunity by different and unique immunomodulatory properties: the presence of tightly controlled physical barriers, the lack of a classical lymphatic drainage system, the presence of functional lymphatic vessels [1], the relative deficiency of constitutive MHC expression, and the immunomodulatory properties regulated via the expression of immunosuppressive proteins [2]. In passive diffusion limited to lipophilic substances, (ii) carrier-mediated transport, and contrast, direct (iii) entry mechanisms Dothelial ‘Trojan horse’ route refers to viruses that(not infect peripheral cells and The entermechanisms the CNS paren- for crossing chyma viaBBB paracellular or transcellular means. RABV and HSV bypass the neuroprotective barriers and enter the CNS via retrograde transport along peripheral nerves (right). The ‘Trojan horse’ route refers to viruses that infect peripheral cells and enter the CNS parenchyma via paracellular or transcellular means. Like RABV, the herpes simplex virus (HSV) invades the CNS by bypassing the BBB via retrograde transport along nerves. Survivors suffer from severe neuropsychological longterm sequelae, including mainly cognitive dysfunctions [52]
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