CD4 deficiency causes poliomyelitis and axonal blebbing in murine coronavirus induced neuroinflammation.

Chakravarty, Debanjana; Saadi, Fareeha; Kundu, Soumya; Bose, Abhishek; Khan, Reas; Dine, Kimberly; Kenyon, Lawrence C; Shindler, Kenneth S; Das Sarma, Jayasri

Mouse hepatitis virus (MHV) is a murine β-coronavirus (m-CoV) which causes a wide range of diseases in mouse and rat, including hepatitis, enteritis, respiratory diseases, and encephalomyelitis in the CNS. MHV infection in mice provides an efficient cause-effect experimental model to understand the mechanisms of direct virus induced neural cell damage leading to demyelination and axonal loss which are pathological features of Multiple sclerosis (MS), the most common disabling neurological disease in young adults. Infiltration of T lymphocytes, activation of microglia and their interplay are the primary pathophysiological events leading to the disruption of myelin sheath in MS. However, there are emerging evidences supporting gray matter involvement and degeneration in MS. The investigation of T cell function in the pathogenesis of deep gray matter damage is necessary. Here, we employed RSA59 (isogenic recombinant strain of MHV-A59) induced experimental neuroinflammation model to compare the disease in CD4-/- mice with CD4+/+ mice at days 5, 10, 15, and 30 p.i. Viral titer estimation, nucleocapsid gene amplification and viral anti-nucleocapsid staining confirm enhanced replication of the virions in the absence of functional CD4+ T cells in the brain. Histopathological analyses showed an elevated susceptibility of CD4-/- mice to axonal degeneration in the CNS with augmented progression of acute poliomyelitis, and dorsal root ganglionic inflammation rarely observed in CD4+/+ mice. Depletion of CD4+ T cells shows unique pathological bulbar vacuolation in the brain parenchyma of infected mice with persistent CD11b+ microglia/macrophages in the inflamed regions on day 30 p.i. In summary, the current study suggests that CD4+ T cells are critical for controlling acute stage poliomyelitis (gray matter inflammation) and chronic axonal degeneration, inflammatory demyelination due to loss of protective anti-viral host immunity.IMPORTANCE The current trend in CNS disease biology is to understand the neural cell-immune interaction to investigate the underlying mechanism of neuroinflammation, rather than focusing on peripheral immune activation. Most studies in MS are targeted towards understanding the involvement of CNS white matter. However, the importance of gray matter damage has become critical in understanding the long-term progressive neurological disorder. Our study highlights the importance of CD4+T cells in safeguarding the neurons against axonal blebbing and poliomyelitis from murine Betacoronavirus-induced neuroinflammation. Current knowledge of the mechanisms that lead to gray matter damage in MS is limited, because the most widely used animal model EAE does not present this aspect of the disease. Our results thus, add to the existing limited knowledge in the field. We also show that the microglia, though important for the initiation of neuroinflammation, cannot establish a protective host immune response without the help of CD4+ T cells.