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An In vitro Model to Study Immune Responses of Human Peripheral Blood Mononuclear Cells to Human Respiratory Syncytial Virus Infection
Published on: December 10, 2013
Correlation between interferon sensitivity of reovirus isolates and ability to discriminate between normal and
1Département de Microbiologie et Immunologie, Université de Montréal, PO Box 6128, Station centre-ville, Montréal, Québec, Canada, H3C 3J7.
Abstract:
Mammalian reoviruses exhibit a propensity to replicate in transformed cells. It is currently believed that the interferon-inducible RNA-dependent protein kinase (PKR), an intracellular host-cell resistance factor that is inhibited by an activated Ras-dependent pathway in transformed cells, is responsible for this discrimination. In the present study, reovirus isolates differing in their sensitivity to interferon were obtained by chemical mutagenesis, and examined for their replicative properties in parental and Ras-transformed mouse NIH-3T3 cells. It was observed that most isolates can bypass resistance mechanisms of parental cells at high m.o.i., and that there is a correlation between the ability to discriminate between transformed and parental cells, and interferon sensitivity. Most interestingly, an interferon-hypersensitive mutant virus was more dependent on Ras activation than any other viral isolate. Altogether, this suggests that optimal reovirus isolates could be selected to attack tumour cells depending on the nature of the alterations in interferon-inducible pathways found in these cells.
Insights
Reoviruses can infect cancer cells by exploiting differences in cellular defenses. Researchers found that certain reovirus strains are better at targeting tumor cells based on their interferon sensitivity and Ras pathway activation.
Area of Science:
- Virology
- Oncology
- Immunology
Background:
- Mammalian reoviruses preferentially replicate in transformed cells.
- Interferon-inducible protein kinase R (PKR) is a host resistance factor.
- Activated Ras pathways in transformed cells inhibit PKR, aiding viral replication.
Purpose of the Study:
- To investigate reovirus isolates' ability to discriminate between normal and transformed cells.
- To understand the role of interferon sensitivity and Ras activation in reovirus replication.
- To identify optimal reovirus strains for targeting tumor cells.
Main Methods:
- Chemical mutagenesis of reovirus to generate isolates with varying interferon sensitivity.
- Assessment of reovirus replication in parental and Ras-transformed NIH-3T3 mouse cells.
- Analysis of viral replication efficiency at high multiplicity of infection (m.o.i.).
Main Results:
- Most reovirus isolates bypassed parental cell resistance mechanisms at high m.o.i.
- A correlation was observed between interferon sensitivity and the ability to discriminate between cell types.
- An interferon-hypersensitive mutant showed increased dependence on Ras activation.
Conclusions:
- Reovirus's ability to target transformed cells is linked to interferon sensitivity.
- Ras pathway activation plays a crucial role in reovirus replication in transformed cells.
- Tailoring reovirus isolates to specific cellular alterations could enhance tumor cell targeting.
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