Aflatoxin B1 and Epstein-Barr virus-induced CCL22 expression stimulates B cell infection.

in Proceedings of the National Academy of Sciences of the United States of America by Mohamed Ali Maroui, Grace Akinyi Odongo, Lucia Mundo, Francesca Manara, Fabrice Mure, Floriane Fusil, Antonin Jay, Tarik Gheit, Thanos M Michailidis, Domenico Ferrara, Lorenzo Leoncini, Paul Murray, Evelyne Manet, Théophile Ohlmann, Marthe De Boevre, Sarah De Saeger, François-Loïc Cosset, Stefano Lazzi, Rosita Accardi, Zdenko Herceg, Henri Gruffat, Rita Khoueiry

TLDR

  • The study found that mycotoxins and a virus called Epstein-Barr Virus (EBV) work together to make a protein called Chemokine ligand 22 (CCL22) that helps cancer cells grow. The study also found that this protein is made by other viral genes in addition to the one that was previously thought to make it. The study also found that this protein helps the virus infect cells. These findings suggest that this protein is important for cancer development.

Abstract

Epstein-Barr Virus (EBV) infects more than 90% of the adult population worldwide. EBV infection is associated with Burkitt lymphoma (BL) though alone is not sufficient to induce carcinogenesis implying the involvement of co-factors. BL is endemic in African regions faced with mycotoxins exposure. Exposure to mycotoxins and oncogenic viruses has been shown to increase cancer risks partly through the deregulation of the immune response. A recent transcriptome profiling of B cells exposed to aflatoxin B1 (AFB1) revealed an upregulation of the Chemokine ligand 22 (CCL22) expression although the underlying mechanisms were not investigated. Here, we tested whether mycotoxins and EBV exposure may together contribute to endemic BL (eBL) carcinogenesis via immunomodulatory mechanisms involving CCL22. Our results revealed that B cells exposure to AFB1 and EBV synergistically stimulated CCL22 secretion via the activation of Nuclear Factor-kappa B pathway. By expressing EBV latent genes in B cells, we revealed that elevated levels of CCL22 result not only from the expression of the latent membrane protein LMP1 as previously reported but also from the expression of other viral latent genes. Importantly, CCL22 overexpression resulting from AFB1-exposure in vitro increased EBV infection through the activation of phosphoinositide-3-kinase pathway. Moreover, inhibiting CCL22 in vitro and in humanized mice in vivo limited EBV infection and decreased viral genes expression, supporting the notion that CCL22 overexpression plays an important role in B cell infection. These findings unravel new mechanisms that may underpin eBL development and identify novel pathways that can be targeted in drug development.

Overview

  • The study investigates the role of mycotoxins and Epstein-Barr Virus (EBV) in the development of Burkitt lymphoma (BL) in African regions. The study uses transcriptome profiling and in vitro experiments to investigate the immunomodulatory mechanisms involved in the synergistic stimulation of Chemokine ligand 22 (CCL22) secretion by mycotoxins and EBV exposure. The study aims to identify new mechanisms that may underpin BL development and novel pathways that can be targeted in drug development.

Comparative Analysis & Findings

  • The study found that B cells exposed to aflatoxin B1 (AFB1) and Epstein-Barr Virus (EBV) synergistically stimulated CCL22 secretion via the activation of Nuclear Factor-kappa B pathway. The study also revealed that elevated levels of CCL22 result not only from the expression of the latent membrane protein LMP1 as previously reported but also from the expression of other viral latent genes. Moreover, the study found that CCL22 overexpression resulting from AFB1-exposure in vitro increased EBV infection through the activation of phosphoinositide-3-kinase pathway. These findings suggest that CCL22 plays an important role in B cell infection and may underpin BL development.

Implications and Future Directions

  • The study's findings have significant implications for the development of new drugs targeting CCL22 and its role in BL development. The study identifies new mechanisms that may underpin BL development and novel pathways that can be targeted in drug development. Future research should focus on the development of drugs that target CCL22 and its role in BL development, as well as the development of drugs that target other viral latent genes involved in BL development.
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