Murine retroviral neurovirulence correlates with an enhanced ability ofvirus to infect selectively, replicate in, and activate resident microglial cells.
To determine the biologic basis of ts1 MoMuLV neurovirulence in vivo, newborn CFW/D mice were inoculated with neurovirulent ts1 MoMuLV and nonneurovirulent wt MoMuLV and the temporal response to virus infection in the central nervous system (CNS), spleen, and thymus was studied comparatively. Experimental procedures included single and double labeling in situ immunohistochemistry with selective morphometric analyses, and steady state immunoblotting of viral proteins. Cellular targets for virus infection were identical for both ts1 and wt MoMuLV and consisted sequentially of 1) splenic megakaryocytes, 2) splenic and thymic lymphocytes, 3) CNS capillary endothelial cells, and 4) CNS pericytes and microglia. Resident microglial cells served as the major reservor and amplifier of virus infection in the CNS of ts1 MoMuLV-infected mice; a similar but much less significant role was played by microglia in wt MoMuLV-infected mice. The genesis and progression of severe spongiform lesions in ts1 MoMuLV-infected mice were both temporally and spatially correlated with amplified virus infection of microglia, and hyperplasia and hypertrophy of both virus-infected and nonvirus-infected microglial cells. Direct virus infection of neurons was never observed. The development of clinical neurologic disease and spongiform lesions in ts1 MoMuLV-infected mice correlated with the accumulation of both viral gag and env gene products in the CNS; there was no selective accumulation of env precursor polyprotein Pr80env. When compared to wt MoMuLV-infected mice, the neurovirulence of ts1 MoMuLV-infected mice occurred by an enhanced ability to replicate in the CNS and to infect and activate more microglia, rather than by a fundamental change in cellular tropism or topography of virus infection.
Baszler
T V
TV
Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Illinois, Urbana.
Zachary
J F
JF
D000818:Animals; D000914:Antibodies, Viral / Q000032:analysis; D002490:Central Nervous System / Q000276:immunology / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology; D002493:Central Nervous System Diseases / Q000382:microbiology* / Q000473:pathology; D015151:Immunoblotting; D007150:Immunohistochemistry; D051379:Mice; D008815:Mice, Inbred Strains; D008979:Moloney murine leukemia virus / Q000276:immunology / Q000472:pathogenicity* / Q000502:physiology; D013154:Spleen / Q000276:immunology; D013950:Thymus Gland / Q000276:immunology; D014764:Viral Proteins / Q000032:analysis; D014774:Virulence; D014779:Virus Replication
D000914:Antibodies, Viral; D014764:Viral Proteins