埃普斯坦－巴尔病毒（EBV）和恶性疟原虫（Plasmodium falciparum）对地方性布尔基特淋巴瘤（BL）的发展具有明确的作用，然而涉及的机制仍然未知。疟疾的主要特征之一是溶血和红细胞旁观者机溶，导致大量游离血红素进入外周血液。我们假设在疟疾感染期间释放的血红素会驱动潜伏感染的EBV阳性B细胞分化，导致病毒重新激活和释放感染性病毒。为验证这一假设，我们使用了EBV阳性的Mutu I B细胞系，用血红素（血红素的氧化形式）进行处理，并评估EBV再激活的证据。血红素处理导致EBV立即早期、早期和晚期裂解基因转录的表达。此外，CD138的表达（浆细胞标记物）与血红素处理的Mutu I细胞上的晚期裂解蛋白gp350共同表达。最后，在上清液中检测到与病毒颗粒产生相关的DNase抗性EBV DNA。为评估血红素处理引起的转录变化，对模拟和血红素处理的Mutu I细胞进行了RNA测序，并鉴定了从成熟B细胞转录到浆细胞转录的转变。为了确定血红素诱导的B细胞分化机制，我们测量了含有特定血红素结合位点的浆细胞转录抑制因子BACH2的水平。血红素处理导致4个BL细胞系（两个EBV阳性，两个EBV阴性）在处理后24小时内BACH2的显著降解。使用siRNA在Mutu I细胞中敲减BACH2显著增加CD138+gp350+细胞的水平，与血红素处理相似。这表明血红素诱导的BACH2降解负责浆细胞分化和病毒再激活。综上所述，这些数据支持一种模型，即通过血红素调节，在疟疾感染期间可发生EBV再激活，提供了疟疾和EBV之间的机制联系。版权声明：© 2023年Burnet等人。本文是按照创作共用许可协议发布的开放获取文章，允许在任何媒体中自由使用、分发和再现，前提是保留原始作者和引用源。

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.Copyright: © 2023 Burnet et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.