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Murine retroviral neurovirulence correlates with an enhanced ability ofvirus to infect selectively, replicate in, and
1Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Illinois, Urbana.
Abstract:
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.
Insights
Neurovirulent Moloney murine leukemia virus (MoMuLV) causes severe spongiform lesions by infecting and activating microglia in the central nervous system (CNS). This enhanced replication in microglia, not altered cell tropism, drives ts1 MoMuLV neurovirulence.
Area of Science:
- Virology
- Neuroscience
- Immunology
Background:
- Murine leukemia viruses (MoMLVs) can cause neurological disease.
- Understanding the specific viral and host factors driving neurovirulence is crucial for developing effective countermeasures.
Purpose of the Study:
- To elucidate the biological basis of ts1 MoMuLV neurovirulence in vivo.
- To compare the temporal response to ts1 MoMuLV and wild-type (wt) MoMuLV infection in the central nervous system (CNS), spleen, and thymus.
Main Methods:
- In situ immunohistochemistry with morphometric analyses.
- Steady-state immunoblotting of viral proteins.
- Comparative analysis of viral infection in newborn mice.
Main Results:
- Cellular targets for ts1 MoMuLV and wt MoMuLV infection were identical, including splenic megakaryocytes, lymphocytes, CNS capillary endothelial cells, pericytes, and microglia.
- Resident microglia were the major reservoir and amplifier of ts1 MoMuLV infection in the CNS.
- Spongiform lesion development correlated with amplified microglial infection and activation, and accumulation of viral gag and env gene products.
Conclusions:
- Ts1 MoMuLV neurovirulence stems from an enhanced ability to replicate in the CNS and infect/activate microglia.
- The study identified microglia as key players in MoMuLV-induced neurodegeneration.
- No fundamental change in cellular tropism or infection topography was observed.