**3. Neurotropic virus infection in mice is employed as an experimental model system to understand the underlying mechanisms of encephalitis, poliomyelitis, neuroinflammation, and demyelination concurrent with axonal loss**

Neuroinflammation is responsible for initiating direct neuroglial dystrophy, which in turn can activate CNS resident microglia to release immune modulators. Microglia, the major resident immune cells in the central nervous system (CNS), are considered as the key cellular mediators of neuroinflammatory processes. Microglial research has become a central focus in cellular neuroimmunology and neuroinflammation in the past few years. Chronic/remitting neurological disease such as multiple sclerosis (MS) has long been considered an inflammatory autoimmune disease with the infiltration of peripheral myelin-specific T cells into the CNS. With the rapid advancement in the field of microglia and astrocytic neurobiology, the term neuroinflammation progressively started to denote chronic CNS cell-specific inflammation in MS. The direct glial responses in MS are different from conventional peripheral immune responses. This book chapter attempts to summarize current findings of neuroinflammatory responses within the CNS by direct infection of neural cells by mouse hepatitis virus (MHV) and the mechanisms by which glial cell responses ultimately contribute to the meningioencephalomyelitis and demyelination concurrent with axonal loss (**Figure 1**). Microglia can be persistently infected by MHV. Microglial activation and phagocytosis are recognized to be critically important in the pathogenesis of

#### **Figure 1.**

*Disease kinetics and pathological manifestations of murine β-CoV, MHV-A59 intracranial inoculation in C57BL/6 mice, a model to understand viral induced meningioencephalomyelitis and demyelination concurrent with axonal loss. (A) Shows the timeline of infection namely acute stage and its corresponding neuropathologies: meningitis denoting inflammation in the meningeal layers, encephalitis,an acute diffuse inflammation of the brain, and inflammation in the spinal cord denoted as myelitis and chronic progressive demyelination characterized by myelin loss concurrent with axonal loss. (B) Kinetics of MHV-A59 replication and viral clearance represented by viral RNA and infectious viral particles respectively and occurrence of demyelination [20].*

demyelination. Emerging evidence for the pathogenic role of microglia and the activation of inflammatory pathways in these cells in MHV infection supports the concept that microglia-induced neuroinflammation is an amplifier of virus-induced neuropathology. Conventional understanding was that the peripheral immune cells are the major players for mounting CNS inflammatory responses. But the current studies revealed that if microglial activation and its immune modulators can check the infection, then the peripheral immune system need not be involved in mounting host immunity, and meningioencephalomyelitis may not shadow. In most cases, CNS resident microglial activation sets the stage for innate immune inflammation that results in the proinflammatory milieu of cytokines and chemokines, known as cytokine storm, which, while trying to combat pathogens, also causes damage to the CNS tissues. Amelioration of the proinflammatory condition requires anti-inflammatory cytokines where the peripheral immune system plays a major role. A series of recent studies on neurotropic murine β-coronavirus demonstrated acute-innate neuroinflammation mediated by CNS resident microglial interplay with peripheral leucocytes comprising monocytes and neutrophils NKT cells, CD4+ and CD8+ T cells to eradicate the pathogen and protect host tissue against aberrant tissue damage (**Figure 2**). In the below-mentioned sections of this book chapter, we are discussing in detail MHV infection as a prototype of β-coronavirus infection and its pathogenesis to understand the underpinning mechanism of meningioencephalomyelitis, demyelination and axonal loss.

#### *Neurotropic Virus-Induced Meningoencephalomyelitis DOI: http://dx.doi.org/10.5772/intechopen.102674*

#### **Figure 2.**

*Temporal kinetics of CNS resident glial cell activation associated with peripheral cell migration in response to RSA59 infection in the mouse CNS is key to cause meningioencephalomyeltits. Intracranial inoculation of RSA59 directly infects CNS resident neuroglial cells that in-turn activates CNS resident immune-glial cells like astrocytes and microglia. Activated CNS resident cells secrete a large number of inflammatory mediators like pro-inflammatory cytokines and chemokines. Microglial activation and its pro-inflammatory mileu in the inflamed CNS make a chemoattractant gradient to help the migration of peripheral leukocytes in the CNS. A differential infiltration of total myeloid (neutrophils, macrophages/monocytes, and microglia) and lymphoid (CD4, CD8, and NKT) cell populations observed at different time post infection is critical for orchestration of the clearance of the viral particle mounting host immunity by balancing the pro-inflammatory condition with the anti-inflammatory condition and restoring the CNS homeostasis.*

#### **3.1 MHV**

Mouse hepatitis virus (MHV) is a β-CoV of the family Coronaviridae. It poses no threat to humans but shows similarities with other human viruses of the same family, such as SARS-CoV, MERS-CoV, and SARS-CoV-2 though they are evolutionarily distinct. MHV can infect the CNS and cause white matter lesions, which makes it an excellent viral model of neuroinflammatory demyelinating disease. Depending on the inoculation route and the strain of MHV-CoV, different outcomes are expected [21].

For example, a highly neurovirulent strain of MHV, JHM, J2.2-V-1, upon intracranial inoculation, induces a monophasic disease course, characterized by inflammatory cell infiltrates in the CNS with subsequent demyelination and clinical symptoms of hind limb weakness, ataxia, and paralysis [22, 23]. No auto-reactive T cells have ever been found in the CNS of J2.2-V-1-infected mice, and the disease is the resultant of virus-specific T cells, which indicated that virus alone can cause myelin destruction. Earlier it was believed that demyelination in JHM infection may be solely due to the lytic oligodendrocyte infection [24], but with the application of immune-deficient animal models, it became clear that immune-mediated mechanisms may be more important [25].

MHV-A59, a hepatotropic and neurotropic MHV strain, caused demyelination in C57BL/6 mice even in the absence of B and T cells [20]. The disease upon MHV-A59 intracranial administration also follows a biphasic course, where encephalomyelitis is characteristic of an acute phase peaking during days 5/6 post infection (p.i.) and chronic stage where demyelination and axonal degeneration peak on day 30 p.i. [26–29]. Thus, it can be said that different, but related MHV strains may induce demyelination via distinct mechanisms. MHV-A59 induced neuroinflammation and neuroimmune modulation mediated neuroglial dystrophy is triggered by the activation of cellular censors like Toll-like receptor (TLRs)/Rig-I-like receptor (RLRs)/synthase for the second messenger cyclic GMP-AMP and the cyclic GMP-AMP receptor stimulator of interferon genes (cGAS-STING) which can further activate the interferon regulatory factors (IRFs), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and downstream type I interferon (IFN) genes. Acute-innate neuroinflammation is rather dependent on the CNS resident immune cell activation in association with peripheral derived myeloid cells, which in turn involve lymphoid cells in ameliorating proinflammatory condition and bring the anti-inflammatory condition in order to restore the homeostasis of the CNS compartment [30].

Studies are focused on understanding mechanisms from cellular sensing to the disease outcome comprising the MHV-A59 induced neuroinflammation encompassing encephalitis and microglial nodule formation and its progressive myelin pathology concurrent with axonal pathology. We have used and compared spike gene recombinant strains of MHV, a demyelinating strain (DM) RSA59, and non-demyelinating strain (NDM) RSMHV2 to understand the genomic control of encephalitic properties. A plethora of studies from the eminent scientists in this field, along with ours, have contributed to understanding the pathogenesis of MHV infection. Strains of MHV can cause direct CNS cell infection or access the CNS via retrograde axonal transport, but irrespective of the route, they cause encephalitis [31–33].
