B-cell-independent lymphoid tissue infection by a B-cell-tropic rhadinovirus

Chao, Brittany; Frederico, Bruno; Stevenson, Philip G.

doi:10.1099/vir.0.000188

Cited by 4 publications

(9 citation statements)

References 29 publications

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“…Numbers of infected B cells were low, as expected at this early time point (16), but cre ϩ and anti-IFNAR-treated mice all showed more B cell infection (B220 ϩ GFP ϩ ) than did cre Ϫ flox-IFNAR controls, so again, IFN-I limited viral spread to B cells.…”

Section: Ifnar Blockade Does Not Change the Predominant Route Of Insupporting

confidence: 67%

“…7). We analyzed spleens at day 4, when infectious virus is passing through myeloid cells (16). Anti-IFNAR treatment increased the titers of infectious virus, consistent with IFN-I restricting lytic MZM infection (9).…”

Section: Ifnar Blockade Does Not Change the Predominant Route Of Inmentioning

confidence: 74%

“…MuHV-4 inoculated intraperitoneally (i.p.) infects the spleen directly (as well as other peritoneal organs) and specifically targets marginal zone (MZ) macrophages (MZM) (15,16). From MZM, infection spreads sequentially to MZ B cells, follicular DC, and then follicular B cells.…”

Section: Importancementioning

confidence: 99%

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Type I Interferon Signaling to Dendritic Cells Limits Murid Herpesvirus 4 Spread from the Olfactory Epithelium

Lawler

Stevenson

2017

J Virol

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Murid herpesvirus 4 (MuHV-4) is a B cell-tropic gammaherpesvirus that can be studied Despite viral evasion, type I interferons (IFN-I) limit its spread. After MuHV-4 inoculation into footpads, IFN-I protect lymph node subcapsular sinus macrophages (SSM) against productive infection; after peritoneal inoculation, they protect splenic marginal zone macrophages, and they limit MuHV-4 replication in the lungs. While invasive infections can be used to test specific aspects of host colonization, it is also important to understand natural infection. MuHV-4 taken up spontaneously by alertmice enters them via olfactory neurons. We determined how IFN-I act in this context. Blocking IFN-I signaling did not increase neuronal infection but allowed the virus to spread to the adjacent respiratory epithelium. In lymph nodes, a complete IFN-I signaling block increased MuHV-4 lytic infection in SSM and increased the number of dendritic cells (DC) expressing viral green fluorescent protein (GFP) independently of lytic infection. A CD11c cell-directed signaling block increased infection of DC only. However, this was sufficient to increase downstream infection, consistent with DC providing the main viral route to B cells. The capacity of IFN-I to limit DC infection indicated that viral IFN-I evasion was only partly effective. Therefore, DC are a possible target for IFN-I-based interventions to reduce host colonization. Human gammaherpesviruses infect B cells and cause B cell cancers. Interventions to block virus binding to B cells have not stopped their infection. Therefore, we must identify other control points that are relevant to natural infection. Human infections are difficult to analyze. However, gammaherpesviruses colonize all mammals. A related gammaherpesvirus of mice reaches B cells not directly but via infected dendritic cells. We show that type I interferons, an important general antiviral defense, limit gammaherpesvirus B cell infection by acting on dendritic cells. Therefore, dendritic cell infection is a potential point of interferon-based therapeutic intervention.

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Section: Ifnar Blockade Does Not Change the Predominant Route Of Insupporting

confidence: 67%

Section: Ifnar Blockade Does Not Change the Predominant Route Of Inmentioning

confidence: 74%

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Type I Interferon Signaling to Dendritic Cells Limits Murid Herpesvirus 4 Spread from the Olfactory Epithelium

Lawler

Stevenson

2017

J Virol

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“…Again blocking IFNAR increased infectious virus titers at d4. Total recoverable virus (infectious centre assay) increased similarly to infectious virus, consistent with most early spleen infection being lytic in MZ macrophages [ 46 ]. By d7 after i.p.…”

Section: Resultsmentioning

confidence: 90%

Type I Interferons Direct Gammaherpesvirus Host Colonization

et al. 2016

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Gamma-herpesviruses colonise lymphocytes. Murid Herpesvirus-4 (MuHV-4) infects B cells via epithelial to myeloid to lymphoid transfer. This indirect route entails exposure to host defences, and type I interferons (IFN-I) limit infection while viral evasion promotes it. To understand how IFN-I and its evasion both control infection outcomes, we used Mx1-cre mice to tag floxed viral genomes in IFN-I responding cells. Epithelial-derived MuHV-4 showed low IFN-I exposure, and neither disrupting viral evasion nor blocking IFN-I signalling markedly affected acute viral replication in the lungs. Maximising IFN-I induction with poly(I:C) increased virus tagging in lung macrophages, but the tagged virus spread poorly. Lymphoid-derived MuHV-4 showed contrastingly high IFN-I exposure. This occurred mainly in B cells. IFN-I induction increased tagging without reducing viral loads; disrupting viral evasion caused marked attenuation; and blocking IFN-I signalling opened up new lytic spread between macrophages. Thus, the impact of IFN-I on viral replication was strongly cell type-dependent: epithelial infection induced little response; IFN-I largely suppressed macrophage infection; and viral evasion allowed passage through B cells despite IFN-I responses. As a result, IFN-I and its evasion promoted a switch in infection from acutely lytic in myeloid cells to chronically latent in B cells. Murine cytomegalovirus also showed a capacity to pass through IFN-I-responding cells, arguing that this is a core feature of herpesvirus host colonization.

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“…When mice lack B cells, SCLN infection remains modest, and splenic viral loads are severely reduced (28,29). Thus, MuHV-4 requires B cell infection for normal systemic infection.…”

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confidence: 99%

Gammaherpesvirus Colonization of the Spleen Requires Lytic Replication in B Cells

Lawler

Miranda

May

et al. 2018

J Virol

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Gammaherpesviruses infect lymphocytes and cause lymphocytic cancers. Murid herpesvirus-4 (MuHV-4), Epstein-Barr virus, and Kaposi's sarcoma-associated herpesvirus all infect B cells. Latent infection can spread by B cell recirculation and proliferation, but whether this alone achieves systemic infection is unclear. To test the need of MuHV-4 for lytic infection in B cells, we flanked its essential ORF50 lytic transactivator with sites and then infected mice expressing B cell-specific Cre (CD19-Cre). The floxed virus replicated normally in Cre mice. In CD19-Cre mice, nasal and lymph node infections were maintained; but there was little splenomegaly, and splenic virus loads remained low. Cre-mediated removal of other essential lytic genes gave a similar phenotype. CD19-Cre spleen infection by intraperitoneal virus was also impaired. Therefore, MuHV-4 had to emerge lytically from B cells to colonize the spleen. An important role for B cell lytic infection in host colonization is consistent with the large CD8 T cell responses made to gammaherpesvirus lytic antigens during infectious mononucleosis and suggests that vaccine-induced immunity capable of suppressing B cell lytic infection might reduce long-term virus loads. Gammaherpesviruses cause B cell cancers. Most models of host colonization derive from cell cultures with continuous, virus-driven B cell proliferation. However, vaccines based on these models have worked poorly. To test whether proliferating B cells suffice for host colonization, we inactivated the capacity of MuHV-4, a gammaherpesvirus of mice, to reemerge from B cells. The modified virus was able to colonize a first wave of B cells in lymph nodes but spread poorly to B cells in secondary sites such as the spleen. Consequently, viral loads remained low. These results were consistent with virus-driven B cell proliferation exploiting normal host pathways and thus having to transfer lytically to new B cells for new proliferation. We conclude that viral lytic infection is a potential target to reduce B cell proliferation.

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B-cell-independent lymphoid tissue infection by a B-cell-tropic rhadinovirus

Cited by 4 publications

References 29 publications

Type I Interferon Signaling to Dendritic Cells Limits Murid Herpesvirus 4 Spread from the Olfactory Epithelium

Type I Interferon Signaling to Dendritic Cells Limits Murid Herpesvirus 4 Spread from the Olfactory Epithelium

Type I Interferons Direct Gammaherpesvirus Host Colonization

Gammaherpesvirus Colonization of the Spleen Requires Lytic Replication in B Cells

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