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Brain infection by neuroinvasive but avirulent murine oncornaviruses
S Asković1, F J McAtee, C Favara
1Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, Hamilton, Montana 59840, USA. saskovic@nih.gov
Abstract:
The chimeric murine oncornavirus FrCas(E) causes a rapidly progressive noninflammatory spongiform encephalomyelopathy after neonatal inoculation. The virus was constructed by the introduction of pol-env sequences from the wild mouse virus CasBrE into the genome of a neuroinvasive but nonneurovirulent strain of Friend murine leukemia virus (FMuLV), FB29. Although the brain infection by FrCas(E) as well as that by other neurovirulent murine retroviruses has been described in detail, little attention has been paid to the neuroinvasive but nonneurovirulent viruses. The purpose of the present study was to compare brain infection by FrCas(E) with that by FB29 and another nonneurovirulent virus, F43, which contains pol-env sequences from FMuLV 57. Both FB29 and F43 infected the same spectrum of cell types in the brain as that infected by FrCas(E), including endothelial cells, microglia, and populations of neurons which divide postnatally. Viral burdens achieved by the two nonneurovirulent viruses in the brain were actually higher than that of FrCas(E). The widespread infection of microglia by the two nonneurovirulent viruses is notable because it is infection of these cells by FrCas(E) which is thought to be a critical determinant of its neuropathogenicity. These results indicate that although the sequence of the envelope gene determines neurovirulence, this effect appears to operate through a mechanism which does not influence either viral tropism or viral burden in the brain. Although all three viruses exhibited similar tropism for granule neurons in the cerebellar cortex, there was a striking difference in the distribution of envelope proteins in those cells in vivo. The FrCas(E) envelope protein accumulated in terminal axons, whereas those of FB29 and F43 remained predominantly in the cell bodies. These observations suggest that differences in the intracellular sorting of these proteins may exist and that these differences appear to correlate with neurovirulence.
Insights
Neurovirulent murine retroviruses cause spongiform encephalomyelopathy. Nonneurovirulent viruses infect similar brain cells but differ in envelope protein distribution, suggesting intracellular sorting impacts neurovirulence.
Area of Science:
- Virology
- Neuroscience
- Molecular Biology
Background:
- The chimeric murine oncornavirus FrCas(E) induces a severe spongiform encephalomyelopathy.
- Neurovirulent murine retroviruses' brain infections are well-studied, unlike less-virulent counterparts.
Purpose of the Study:
- Compare brain infection by FrCas(E) with two nonneurovirulent murine leukemia viruses (FMuLV): FB29 and F43.
- Investigate the role of viral tropism, burden, and envelope protein distribution in neurovirulence.
Main Methods:
- Neonatal inoculation of mice with FrCas(E), FB29, and F43.
- Analysis of infected cell types, viral burdens, and envelope protein localization in the brain.
Main Results:
- FB29 and F43 infected similar brain cell types (endothelial cells, microglia, postnatal neurons) as FrCas(E).
- Nonneurovirulent viruses FB29 and F43 achieved higher viral burdens in the brain than FrCas(E).
- FrCas(E) envelope protein accumulated in terminal axons, while FB29 and F43 proteins localized to cell bodies in cerebellar granule neurons.
Conclusions:
- Envelope gene sequence determines neurovirulence, but not through viral tropism or brain burden.
- Differences in intracellular envelope protein sorting correlate with neurovirulence, suggesting a key mechanism.