Extracellular matrix in the CNS induced by neuropathogenic viral infection

Abstract

During the early phase of infection with an extremely neurovirulent murine coronavirus, cl-2, the ER-TR7 antigen (ERag)-positive fibers (ERfibs) associated with laminin and collagen III show a rapid increase in expression levels in the meninges, followed by an appearance of the antigens in the ventricle and brain parenchyma. Then, cl-2 invades the ventricle and ventricular wall along the newly assembled ERfibs after infection, using them as a pathway from the meninges, the initial site of infection. In the lymph nodes and spleen, ERag is mainly produced by fibroblastic reticular cells (FRCs), which play a key role in nursing the ERfibs to form a fibroblastic reticular network (FRN). The FRN functions as a conduit system to transfer antigens, cytokines or leukocytes in the lymphoid organs. In the brain parenchyma, astrocytes were found to produce the main components of mature ERfibs, such as collagen, laminin and ERag, which have been identified in the lymphoid organs. The producibility of these extracellular matrices (ECMs) by astrocytes was further confirmed by primary brain cultures, which disclosed the dissociation of laminin and ERag production, and the close association of ERag production with that of collagen, forming a fibrous structure. The pattern of ECM production in vitro indicated the process of forming mature ERfibs in the brain, that is, fibers made of collagen fibers and ERag are wrapped by laminin prepared as a sheet structure. In addition, the brain parenchymal cells that produce interferon β after infection in spite of their residence away from the sites of viral invasion were surrounded by ERfibs, which were closely associated with astrocytic fibers. These findings indicate that astrocytes play a central role in forming the astrocytic reticular network (ARN) in the brain parenchyma, as FRCs do to form FRN in the lymphoid organs.

IL‐10 expression in pyramidal neurons after neuropathogenic coronaviral infection

“…IL‐6 and MCP‐1 were expressed in none and all of the subregions of the hippocampus, respectively (Table ). IFN‐β was not detected in the hippocampus at 3 dpi (Table ), although its expression was observed in the pons both in the areas adjacent to viral antigen‐positive cells and at a distance from infected sites in astrocytes and in neurons (Supplemental Fig. 1C), as reported …”

“…Furthermore, it was the pyramidal neurons that expressed IL‐10 and not CD11b‐positive Mo/Mas, which can migrate into the hippocampus. The failure of the production of anti‐inflammatory cytokines by Mo/Mas or microglia after infection was also detected by the brain primary culture, where a large population of CD‐11b‐positive cells are found, although we have shown, for the first time, that coronaviral infection can trigger the production of anti‐inflammatory cytokines by Mo/Mas in PECs within 8 h post‐infection (hpi) . The answer to the question of how information on infection reaches the hippocampus is provided by our previous reports .…”

“…The failure of the production of anti‐inflammatory cytokines by Mo/Mas or microglia after infection was also detected by the brain primary culture, where a large population of CD‐11b‐positive cells are found, although we have shown, for the first time, that coronaviral infection can trigger the production of anti‐inflammatory cytokines by Mo/Mas in PECs within 8 h post‐infection (hpi) . The answer to the question of how information on infection reaches the hippocampus is provided by our previous reports . As early as 12 hpi with cl‐2, a unique reticular network (RN) is formed in the meninges, ventricle, ventricular wall, and brain surface facing the meninges, which extends deep into the brain parenchyma with an association with astrocytic fibers within 48 hpi .…”

“…The FRN functions as a conduit system, transferring substances such as cytokines and antigens to facilitate immune responses, and guiding the homing of leukocytes . The RN in the brain, referred to as astrocytic RN (ARN), could have quickly transferred the information about the viral invasion to the cells deep in the brain parenchyma, like FRN does in the lymphoid organs. In addition, cell‐to‐cell‐mediated cross‐talk, like that occurring through an immune synapse formed between lymphoid cells, using either immune‐related or non‐immune‐related molecules such as neurotransmitters, might contribute to transmit the signal from the infected site to neurons in the hippocampus in order to produce IL‐10.…”