A single mutation in the mammalian orthoreovirus S1 gene is responsible for increased interferon sensitivity in a virus mutant selected in Vero cells

Lanoie, Delphine; Côté, Stéphanie; Degeorges, Emmanuelle; Lemay, Guy

doi:10.1016/j.virol.2018.12.010

Cited by 8 publications

(9 citation statements)

References 79 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The s1s protein facilitates reovirus dissemination in the face of IFN-1 responses in vivo. Our data and published studies (32) indicate that s1s contributes to reovirus IFN-1 resistance in cultured cells. To determine whether σ1s is required for reovirus to overcome IFN-1 responses in vivo, we assessed T1L and T1L σ1s-null spread in wild-type and IFNAR1 -/mice (Fig 3).…”

Section: Resultssupporting

confidence: 82%

Lymphatic type-1 interferon responses are critical for control of systemic reovirus dissemination

Phillips

Zita

Howells

et al. 2020

Preprint

View full text Add to dashboard Cite

Mammalian orthoreovirus (reovirus) spreads from the site of infection to every organ system in the body via the blood. However, mechanisms that underlie reovirus hematogenous spread remain undefined. Non-structural protein σ1s is a critical determinant of reovirus bloodstream dissemination that is required for efficient viral replication in many types of cultured cells. Here, we used the specificity of the σ1s protein for promoting hematogenous spread as a platform to uncover a role for lymphatic type-1 interferon (IFN-1) responses in limiting reovirus systemic dissemination. We found that replication of a σ1s-deficient reovirus was restored to wild-type levels in cells with defective type-1 interferon a-receptor (IFNAR1) signaling. In vivo, reovirus spreads systemically following oral inoculation of neonatal mice, whereas the σ1s-null virus remains localized to the intestine. We found that σ1s enables reovirus spread in the presence of a functional IFN-1 response, as the σ1s-deficient reovirus disseminated comparably to wild-type virus in IFNAR1-/- mice. Lymphatics are hypothesized to mediate reovirus spread from the intestine to the bloodstream. IFNAR1 deletion from cells expressing lymphatic vessel endothelium receptor-1 (LYVE-1), a marker for lymphatic endothelial cells, enabled the σ1s-deficient reovirus to disseminate systemically. Together, our findings indicate that IFN-1 responses in lymphatics limit reovirus dissemination. Our data further suggest that the lymphatics are an important conduit for reovirus hematogenous spread.IMPORTANCEType-1 interferon (IFN-1) responses are a critical component of the host response to viral infections. However, the contribution of specific cell and tissue types to control of viral infections is not known. Here, we found that reoviruses lacking nonstructural protein were more sensitive to IFN-1 responses than wild-type reovirus, indicating that σ1s is important for reovirus resistance to IFN-1 responses. The σ1s protein also is a key determinant of reovirus systemic spread. We used tissue-specific IFNAR1 deletion in combination with the IFN-1-sensitive σ1s-null reovirus as a tool to identify a role for lymphatics in reovirus dissemination. We used Cre-lox technology to delete type-1 interferon a-receptor (IFNAR1) in lymphatic cells and found that the IFN-1-sensitive σ1s-deficient reovirus disseminated in mice with lymphatic endothelial cells-specific deletion of IFNAR1. Together, our results indicate that IFN-1 responses in lymphatics are critical for controlling reovirus systemic spread.

show abstract

Section: Resultssupporting

confidence: 82%

Lymphatic type-1 interferon responses are critical for control of systemic reovirus dissemination

Phillips

Zita

Howells

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…In the course of our work on the adaptation of reovirus to different host cells, the Vero cell-adapted virus (VeroAV) was obtained [113,114,115]. Although the virus does not induce more interferon, it turned out to be significantly more sensitive to interferon treatment.…”

Section: Reovirus Proteins Involved In the Control Of The Interfermentioning

confidence: 99%

“…Using plasmid-based reverse genetics, the interferon sensitivity phenotype of VeroAV was attributed solely to one of the two nucleotide substitutions found in its S1 gene. This substitution was responsible for both a Q78P amino acid change in σ1 and a N59H amino acid change in the small σ1s protein encoded in the second overlapping reading frame of S1 [115]. The second substitution observed in S1 resulted in a N198K amino acid change that was shown to be responsible for a better infectivity, especially on Vero cells, due to increased binding to sialic acids at the cell surface [114].…”

Section: Reovirus Proteins Involved In the Control Of The Interfermentioning

confidence: 99%

“…This could somehow counterbalance the loss or the altered functional properties of σ1s. In fact, the σ1s-N59H substitution of VeroAV by itself or the introduction of a stop codon to abolish the expression of σ1s were both shown to decrease cell lysis of infected L929 cells [115]. It should also be mentioned that, during the establishment of viral persistence on Vero cells, the N198K substitution appeared before the Q78P/N59H substitution [113,114].…”

Section: Reovirus Proteins Involved In the Control Of The Interfermentioning

confidence: 99%

See 1 more Smart Citation

How Many Mammalian Reovirus Proteins are involved in the Control of the Interferon Response?

et al. 2019

Self Cite

View full text Add to dashboard Cite

As with most viruses, mammalian reovirus can be recognized and attacked by the host-cell interferon response network. Similarly, many viruses have developed resistance mechanisms to counteract the host-cell response at different points of this response. Reflecting the complexity of the interferon signaling pathways as well as the resulting antiviral response, viruses can—and often have—evolved many determinants to interfere with this innate immune response and allow viral replication. In the last few years, it has been evidenced that mammalian reovirus encodes many different determinants that are involved in regulating the induction of the interferon response or in interfering with the action of interferon-stimulated gene products. In this brief review, we present our current understanding of the different reovirus proteins known to be involved, introduce their postulated modes of action, and raise current questions that may lead to further investigations.

show abstract

“…It was also recently reported that another viral protein, the σ1s protein, contributes to efficient synthesis of viral proteins, at least in some cell types [154]. The mechanism involved is unknown although σ1s apparently also contributes to the control of the antiviral activity of interferon [155]. The importance of interferon in the control of protein synthesis is further discussed in Section 7.4.…”

Section: Protein Synthesis In Reovirus-infected Cellsmentioning

confidence: 99%

Synthesis and Translation of Viral mRNA in Reovirus-Infected Cells: Progress and Remaining Questions

Lemay

2018

Viruses

Self Cite

View full text Add to dashboard Cite

At the end of my doctoral studies, in 1988, I published a review article on the major steps of transcription and translation during the mammalian reovirus multiplication cycle, a topic that still fascinates me 30 years later. It is in the nature of scientific research to generate further questioning as new knowledge emerges. Our understanding of these fascinating viruses thus remains incomplete but it seemed appropriate at this moment to look back and reflect on our progress and most important questions that still puzzle us. It is also essential of being careful about concepts that seem so well established, but could still be better validated using new approaches. I hope that the few reflections presented here will stimulate discussions and maybe attract new investigators into the field of reovirus research. Many other aspects of the viral multiplication cycle would merit our attention. However, I will essentially limit my discussion to these central aspects of the viral cycle that are transcription of viral genes and their phenotypic expression through the host cell translational machinery. The objective here is not to review every aspect but to put more emphasis on important progress and challenges in the field.

show abstract

A single mutation in the mammalian orthoreovirus S1 gene is responsible for increased interferon sensitivity in a virus mutant selected in Vero cells

Cited by 8 publications

References 79 publications

Lymphatic type-1 interferon responses are critical for control of systemic reovirus dissemination

Lymphatic type-1 interferon responses are critical for control of systemic reovirus dissemination

How Many Mammalian Reovirus Proteins are involved in the Control of the Interferon Response?

Synthesis and Translation of Viral mRNA in Reovirus-Infected Cells: Progress and Remaining Questions

Contact Info

Product

Resources

About