Hemin treatment drives viral reactivation and plasma cell differentiation of EBV latently infected B cells.
Epstein-Barr virus (EBV) and Plasmodium falciparum have a well described role in the development of endemic Burkitt lymphoma (BL), yet the mechanisms involved remain unknown. A major hallmark of malarial disease is hemolysis and bystander eryptosis of red blood cells, which causes release of free he...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2023-08-01
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| Series: | PLoS Pathogens |
| Online Access: | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1011561&type=printable |
| _version_ | 1797676569431375872 |
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| author | Anna M Burnet Tonya Brunetti Rosemary Rochford |
| author_facet | Anna M Burnet Tonya Brunetti Rosemary Rochford |
| author_sort | Anna M Burnet |
| collection | DOAJ |
| description | Epstein-Barr virus (EBV) and Plasmodium falciparum have a well described role in the development of endemic Burkitt lymphoma (BL), yet the mechanisms involved remain unknown. A major hallmark of malarial disease is hemolysis and bystander eryptosis of red blood cells, which causes release of free heme in large quantities into peripheral blood. We hypothesized that heme released during malaria infection drives differentiation of latently infected EBV-positive B cells, resulting in viral reactivation and release of infectious virus. To test this hypothesis, we used the EBV-positive Mutu I B-cell line and treated with hemin (the oxidized form of heme) and evaluated evidence of EBV reactivation. Hemin treatment resulted in the expression of EBV immediate early, early and late lytic gene transcripts. In addition, expression of CD138, a marker of plasma cells was co-expressed with the late lytic protein gp350 on hemin treated Mutu I cells. Finally, DNase-resistant EBV DNA indicative of virion production was detected in supernatant. To assess the transcriptional changes induced by hemin treatment, RNA sequencing was performed on mock- and hemin-treated Mutu I cells, and a shift from mature B cell transcripts to plasma cell transcripts was identified. To identify the mechanism of hemin-induced B cell differentiation, we measured levels of the plasma cell transcriptional repressor, BACH2, that contains specific heme binding sites. Hemin treatment caused significant degradation of BACH2 by 24 hours post-treatment in four BL cell lines (two EBV positive, two EBV negative). Knockdown of BACH2 in Mutu I cells using siRNAs significantly increased CD138+gp350+ cells to levels similar to treatment with hemin. This suggested that hemin induced BACH2 degradation was responsible for plasma cell differentiation and viral reactivation. Together, these data support a model where EBV reactivation can occur during malaria infection via heme modulation, providing a mechanistic link between malaria and EBV. |
| first_indexed | 2024-03-11T22:30:06Z |
| format | Article |
| id | doaj.art-a3486e62d9fa450e83ddfc63f2d4fd76 |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-03-11T22:30:06Z |
| publishDate | 2023-08-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-a3486e62d9fa450e83ddfc63f2d4fd762023-09-23T05:30:43ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742023-08-01198e101156110.1371/journal.ppat.1011561Hemin treatment drives viral reactivation and plasma cell differentiation of EBV latently infected B cells.Anna M BurnetTonya BrunettiRosemary RochfordEpstein-Barr virus (EBV) and Plasmodium falciparum have a well described role in the development of endemic Burkitt lymphoma (BL), yet the mechanisms involved remain unknown. A major hallmark of malarial disease is hemolysis and bystander eryptosis of red blood cells, which causes release of free heme in large quantities into peripheral blood. We hypothesized that heme released during malaria infection drives differentiation of latently infected EBV-positive B cells, resulting in viral reactivation and release of infectious virus. To test this hypothesis, we used the EBV-positive Mutu I B-cell line and treated with hemin (the oxidized form of heme) and evaluated evidence of EBV reactivation. Hemin treatment resulted in the expression of EBV immediate early, early and late lytic gene transcripts. In addition, expression of CD138, a marker of plasma cells was co-expressed with the late lytic protein gp350 on hemin treated Mutu I cells. Finally, DNase-resistant EBV DNA indicative of virion production was detected in supernatant. To assess the transcriptional changes induced by hemin treatment, RNA sequencing was performed on mock- and hemin-treated Mutu I cells, and a shift from mature B cell transcripts to plasma cell transcripts was identified. To identify the mechanism of hemin-induced B cell differentiation, we measured levels of the plasma cell transcriptional repressor, BACH2, that contains specific heme binding sites. Hemin treatment caused significant degradation of BACH2 by 24 hours post-treatment in four BL cell lines (two EBV positive, two EBV negative). Knockdown of BACH2 in Mutu I cells using siRNAs significantly increased CD138+gp350+ cells to levels similar to treatment with hemin. This suggested that hemin induced BACH2 degradation was responsible for plasma cell differentiation and viral reactivation. Together, these data support a model where EBV reactivation can occur during malaria infection via heme modulation, providing a mechanistic link between malaria and EBV.https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1011561&type=printable |
| spellingShingle | Anna M Burnet Tonya Brunetti Rosemary Rochford Hemin treatment drives viral reactivation and plasma cell differentiation of EBV latently infected B cells. PLoS Pathogens |
| title | Hemin treatment drives viral reactivation and plasma cell differentiation of EBV latently infected B cells. |
| title_full | Hemin treatment drives viral reactivation and plasma cell differentiation of EBV latently infected B cells. |
| title_fullStr | Hemin treatment drives viral reactivation and plasma cell differentiation of EBV latently infected B cells. |
| title_full_unstemmed | Hemin treatment drives viral reactivation and plasma cell differentiation of EBV latently infected B cells. |
| title_short | Hemin treatment drives viral reactivation and plasma cell differentiation of EBV latently infected B cells. |
| title_sort | hemin treatment drives viral reactivation and plasma cell differentiation of ebv latently infected b cells |
| url | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1011561&type=printable |
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