Cytopathy of an infiltrating monocyte lineage during the early phase of infection with murinecoronavirus in the brain

Abstract

Viral spread during the early stages after infection was compared between a highly neurovirulent mouse hepatitis virus (MHV), JHMV cl-2 strain (cl-2), and its low-virulent mutant, soluble-receptor-resistant (srr)7. The infection of cells with srr7 (soluble-receptor-resistant mutant 7) is dependent on a known MHV receptor (MHVR), carcinoembryonic cell adhesion molecule 1a, whereas cl-2 shows MHVR-independent infection. Initial viral antigens were detected between 12 and 24 h post-inoculation (p.i) in the infiltrating cells that appeared in the subarachnoidal space of mouse brains infected with viruses. There were no significant differences in the intensity or spread of viral antigens in the inflammatory cells between the two viruses. However, 48 h after infection with cl-2, viral antigen-positive cells in the grey matter with the shape of neurons, which do not express MHVR, were detected, while srr7 infection was observed primarily in the white matter. Some of the viral antigen-positive inflammatory cells found in the subarachnoidal space during the early phase of infection reacted with anti-F4/80 or anti-CD11b monoclonal antibodies. Syncytial giant cells (SGCs) expressing viral and CD11b antigens were also detected among these inflammatory cells. These antigen-positive cells appeared in the subarachnoidal space prior to viral antigen spread into the brain parenchyma, indicating that viral encephalitis starts with the infection of infiltrating monocytes which express MHVR. Furthermore, the observation indicates that viral infection has cytopathic effects on the monocyte lineage, which plays a critical role in innate immunity, leading to the rapid spread of viruses during the early stage of infection.

Mutant Murine Hepatitis Virus-Induced Apoptosis in the Hippocampus

“…Neuropathological imaging after infection with srr7 and cl-2 showed that srr7 induced lesions in the cerebral white matter without infecting neurons, which do not express carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM-1), a major MHV receptor (MHVR). In contrast, cl-2 causes necrosis primarily in the gray matter by infecting neurons in an MHVR-independent manner (1,3). The MHVR-dependency and -independency of srr7 and cl-2 infections, or of other JHMV strains, cause in vitro infections of BHK cells, which are MHVR-negative (4-7).…”

“…These differences in neuropathogenesis and MHVR-dependency between srr7 and cl-2 are attributed to a single mutation in the S2 gene (2) within the S protein-encoding region (S gene). The S gene has a high mutation rate (8) and we have obtained several mutant viruses after re-cloning of an srr7 viral stock (maintained in our laboratory for over 10 years) through repeated passages (3,7). All of the isolated mutant viruses (Br-1, Mu-1, and Mu-2) had single or double amino acid substitutions in the S protein, which, compared with the maternal srr7, helped them gain increased virulence and an MHVR-independent manner of infection (7).…”

Contribution of Lewis X Carbohydrate Structure to Neuropathogenic Murine Coronaviral Spread

“…It should be noted that most of the syncytia formed after infection of TGPECs expressed Gr-1 antigen. The main target among leukocytes of MHV-JHM infection has been believed to be the lineages of Mo/Mas, including microglia in the brain (5,29), which express CEACAM1. CEACAM1 is also detectable as an adhesion molecule on Gr-1-positive human granulocytes (22).…”

“…Instead, it produces necrotic lesions in the grey matter with infected neurons, which do not express the major MHV receptor carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) (3,4). A mutant clone isolated from cl-2, srr7, shows attenuated neurovirulence compared to cl-2, although its virulence is still higher than that of the other JHMs, exhibiting rapid viral spread from one organ to another non-adjacent organ within 12 hours after infection, designated as super-acute spread (5). Most of the mice infected with srr7 survive for more than 7 days and die within 10 dpi.…”

“…Initial viral antigens, after inoculation with either cl-2 or srr7, are detectable in CD11b-or F4/80-positive monocytes/ macrophages (Mo/Mas) that have infiltrated the meninges. Syncytial giant cells formed of infected Mo/ Mas are often found in the meninges and ventricular cavity (5).…”