Disruption of Type III Interferon (IFN) Genes
            <i>Ifnl2</i>
            and
            <i>Ifnl3</i>
            Recapitulates Loss of the Type III IFN Receptor in the Mucosal Antiviral Response

Peterson, Stefan T.; Kennedy, Elizabeth A.; Brigleb, Pamela H; Taylor, Gwen M.; Urbanek, Kelly; Bricker, Traci L.; Lee, Sang‐Hyun; Shin, Haina; Dermody, Terence S.; Boon, Adrianus C. M.; Baldridge, Megan T.

doi:10.1128/jvi.01073-19

Cited by 40 publications

(37 citation statements)

References 48 publications

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“…Finally, our studies use neonatal mice and adult tissue-resident macrophages would not be involved in dissemination. shedding (41,42,54). We found no difference in viral intestinal titers between wild-type and σ1s-deficient viruses in wild-type or IFNAR1-knockout mice.…”

Section: Discussionmentioning

confidence: 53%

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

Phillips

Zita

Howells

et al. 2020

Preprint

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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: Discussionmentioning

confidence: 53%

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

Phillips

Zita

Howells

et al. 2020

Preprint

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show abstract

“…In the intestine, reovirus is transcytosed by microfold cells (M-cells) in the gut-associated lymphoid tissue (GALT) where it infects the basolateral surface of IECs (8). Replication in IECs mediates reovirus release into the stool for dissemination to future hosts (8,41,42). To disseminate, reovirus is taken up by cells in the Peyer's patch (4,10,18) and hypothesized to traffic through the MLN via the lymphatics and then to the bloodstream (8).…”

Section: Discussionmentioning

confidence: 99%

“…However, why s1s is dispensable for reovirus replication in the intestine remains an open question. One possibility is that reovirus replication in the intestine is largely controlled by interferon-λ (IFN-λ), as opposed to IFN-1 (41,42,49). Expression of the IFN-λ receptor, IFN-λ receptor 1 (IFNLR1), is largely restricted to the epithelial compartment, which also lacks IFNAR expression (50,51).…”

Section: Discussionmentioning

confidence: 99%

Lymphatic Type 1 Interferon Responses Are Critical for Control of Systemic Reovirus Dissemination

Phillips

Zita

Howells

et al. 2021

J Virol

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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 α-receptor (IFNAR1) signaling. 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. IMPORTANCE Type-1 interferons (IFN-1) are critical host responses to viral infection. However, the contribution of IFN-1 responses to control of viruses in specific cell and tissue types is not fully defined. Here, we identify IFN-1 responses in lymphatics as important for limiting reovirus dissemination. We found that nonstructural protein σ1s enhances reovirus resistance to IFN-1 responses, as a reovirus mutant lacking σ1s was more sensitive to IFN-1 than wild-type virus. In neonatal mice, σ1s is required for reovirus systemic spread. We used tissue-specific IFNAR1 deletion in combination with the IFN-1-sensitive σ1s-null reovirus as a tool to test how IFN-1 responses in lymphatics affect reovirus systemic spread. Deletion of the type-1 interferon α-receptor (IFNAR1) in lymphatic cells using Cre-lox technology enabled dissemination of the IFN-1-sensitive σ1s-deficient reovirus. Together, our results indicate that IFN-1 responses in lymphatics are critical for controlling reovirus systemic spread.

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“…Gut mucosal epithelial cells depend on type-III IFN to protect against viral pathogens. 65 , 66 An antiviral role for IFN-λ has been described in other tissues and cell lineages including human placental trophoblast protection against Zika virus 67 and in vitro human cervical epithelial cell resistance to dengue virus. 68 IFN-λ in murine mammary epithelial cells recruits CD4 + T cells to the tumor microenvironment.…”

Section: Discussionmentioning

confidence: 99%

Doxorubicin Conjugation to Reovirus Improves Oncolytic Efficacy in Triple-Negative Breast Cancer

Berry

Muñoz

Stewart

et al. 2020

Molecular Therapy - Oncolytics

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Breast cancer is the second leading cause of cancer-related deaths in women in the United States. The triple-negative breast cancer (TNBC) subtype associates with higher rates of relapse, shorter overall survival, and aggressive metastatic disease. Hormone therapy is ineffective against TNBC, leaving patients with limited therapeutic options. Mammalian orthoreovirus (reovirus) preferentially infects and kills transformed cells, and a genetically engineered reassortant reovirus infects and kills TNBC cells more efficiently than prototypical strains. Reovirus oncolytic efficacy is further augmented by combination with topoisomerase inhibitors, including the frontline chemotherapeutic doxorubicin. However, long-term doxorubicin use correlates with toxicity to healthy tissues. Here, we conjugated doxorubicin to reovirus (reo-dox) to control drug delivery and enhance reovirus-mediated oncolysis. Our data indicate that conjugation does not impair viral biology and enhances reovirus oncolytic capacity in TNBC cells. Reo-dox infection promotes innate immune activation, and crosslinked doxorubicin retains DNA-damaging properties within infected cells. Importantly, reovirus and reo-dox significantly reduce primary TNBC tumor burden in vivo , with greater reduction in metastatic burden after reo-dox inoculation. Together, these data demonstrate that crosslinking chemotherapeutic agents to oncolytic viruses facilitates functional drug delivery to cells targeted by the virus, making it a viable approach for combination therapy against TNBC.

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Disruption of Type III Interferon (IFN) Genes Ifnl2 and Ifnl3 Recapitulates Loss of the Type III IFN Receptor in the Mucosal Antiviral Response

Cited by 40 publications

References 48 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

Lymphatic Type 1 Interferon Responses Are Critical for Control of Systemic Reovirus Dissemination

Doxorubicin Conjugation to Reovirus Improves Oncolytic Efficacy in Triple-Negative Breast Cancer

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