For reovirus, one amino acid can change everything!

Significance 

Studies have shown that for several viruses, multiple viral genes are involved in the regulation of the innate immune response that is mediated by the interferon response. This response is a major determinant of the pathogenicity of viruses; it also contributes to the ability of certain viruses to distinguish between cancer cells and parental cells. Some researchers have stated that an in-depth understanding of this determinant is quintessential to the conduction of epidemiological surveillance as well as the successful optimization and selection of appropriate viral strains for the treatment of different types of cancer.

In view of this, virologists have begun to explore the possible use of oncolytic viruses (such as mammalian orthoreovirus) for the treatment of cancer. Mammalian orthoreovirus is considered to be an appropriate oncolytic virus for cancer treatment because it is non-pathogenic to humans. However, previous studies have indicated the possible emergence of novel mammalian orthoreovirus strains that may be pathogenic to humans. Moreover, interferon-mediated immune response may be involved in the emergence of pathogenic viral strains. These possibilities necessitate the conduction of further research studies to fully understand the viral determinants that regulate the induction of interferon response and the susceptibility of different viruses to this response.

Recently scientists at University of Montreal Delphine Lanoie, Stéphanie Côté, Emmanuelle Degeorges and led by professor Guy Lemay from the Department of Microbiology demonstrated that the single mutation of the S1 gene is solely responsible for increased interferon sensitivity in a mammalian orthoreovirus mutant previously selected in Vero cells that are deficient in the interferon response. The authors used a combination of whole-genome sequencing and reverse genetics techniques to identify the unique mutation that occurred in the S1 gene that resulted in increased interferon sensitivity in this virus compared to its parental wild-type counterpart.

The research team observed that the rescued Vero-cell-adapted virus (VeroAV) induced a similarly low amount of interferon as the control rescued wild-type virus. However, the rescued Vero-cell-adapted virus (VeroAV) was a hundred fold more sensitive compared to the wild-type.

The researchers also reported that introducing the VeroAV M1, M2 or M3 gene into the wild-type background from which the Vero-cell-adapted virus (VeroAV) was initially derived had no effect on the interferon sensitivity. Whereas, the sole introduction of VeroAV S1 and M2 resulted in a virus that is as sensitive as the rescued Vero-cell-adapted virus (VeroAV). The other five viral genes were identical between the two viruses. Moreover, they observed that the substitution of Q78P of σ1 (N59H in σ1s) in the S1 gene was required to fully reconstitute the interferon sensitivity of the rescued Vero-cell-adapted virus (VeroAV), while complete knockout of σ1s expression also resulted in interferon sensitivity.

The findings of professor Guy Lemay and his research team provided compelling evidence that the mutation of the S1 gene in the rescued Vero-cell-adapted virus (VeroAV) is solely responsible for increased interferon sensitivity in the virus. They also suggest a novel function of σ1s in the control of interferon sensitivity. These findings are important and could lead to further studies on the applications of viruses as potential oncolytic agents and the development of better adapted viruses as effective treatment solutions to different types of cancer.

For reovirus, one amino acid can change everything- Medicine Innovates

About the author

Guy Lemay holds a bachelor’s degree (1980) and a master’s degree (1984) in microbiology and immunology from the Université de Montréal. Subsequently, he pursued his doctoral studies (1987) under the direction of the late Professor Stewart Millward at the Department of Biochemistry, of McGill University. His work then allowed to demonstrate the importance of a reovirus protein in the control of protein synthesis during infection. He subsequently developed his expertise in enzymology and protein biochemistry during a postdoctoral fellowship (1987-1989) under the supervision of Professor Guy Boileau at the Department of Biochemistry of Université de Montréal. He was subsequently recruited as an assistant professor in the Department of Microbiology and Immunology of Université de Montréal in 1989 and promoted to full professor in 2000. As the recipient of a scholarship from the Fonds de recherche en santé du Québec from 1991 to 2003, he developed several research aspects mainly on replication of mammalian retroviruses and reoviruses.

Recently, most of his research is focused on the replication of the latter viruses to better understand their interaction with the host-cell interferon response and their ability to destroy cancer cells. Guy Lemay is the author of more than 75 publications in world-class journals and of 125 scientific communications. In recent years he has been actively involved in communication to lay audiences and the excellence of his teaching activities has been recognized by a prize from the Université de Montréal in 2015. Over the years, he has also been actively involved in his institution by taking charge of graduate and undergraduate programs and as departmental chair, among others.

Reference

Lanoie, D., Côté, S., Degeorges, E., and Lemay, G. A single mutation in the mammalian orthoreovirus S1 gene is responsible for increased interferon sensitivity in a virus mutant selected in Vero cells, Virology 528 (2019) 73-79.

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