RNA transfer by Epstein-Barr virus triggers early events that regulate cell fate and promote immune evasion

Jochum, Simon (2011): RNA transfer by Epstein-Barr virus triggers early events that regulate cell fate and promote immune evasion. Dissertation, LMU München: Fakultät für Chemie und Pharmazie

Abstract

More than 90% of the worldwide population is infected with Epstein Barr virus (EBV). In general, the infection remains asymptomatic and the virus persists for life in latently infected B cells. During this state, viral activity is reduced to the maintenance of the viral genome such that EBV-infected cells are not efficiently recognized by the immune system. However, the first days of primary infection are characterized by a period of lytic gene expression that contributes to successful virus establishment (Kalla et al., 2010). The abundant expression of “foreign” protein renders the infected cell prone to immune recognition and requires viral counter-measures to evade immune responses. The first part of this work focuses on the importance of two immune evasins of EBV during this early phase of infection: BCRF1 and BNLF2a, encoding the viral homologue of the anti-inflammatory cytokine IL-10 and a unique inhibitor of epitope loading on MHC I molecules, respectively. To study their impact on immune responses to freshly infected B cells, I generated recombinant EBV mutants, which are deficient in expressing either BCRF1 or BNLF2a or both. I observed significant immunological consequences during the first days of infection, but, unexpectedly, the MHC I surface pattern of infected B cells was not affected. Deficiency in BNLF2a expression in infected cells resulted in a drastically increased response of EBV-specific CD8+ T cells. BCRF1 did not participate in this effect, but instead severely impaired the cytokine response to viral infection and protected infected cells from elimination by NK/NKT cells. Thus, both immune evasins have important functions during the early phase of infection and are instrumental for the establishment of latency. Their balanced activity illustrates the perfect adaptation of the virus to the host’s immune system. The second part of this work builds upon my initial observation that viral transcripts are present in the infected cell almost instantly following virus entry. I found that EBV particles represent the source of these transcripts as I identified them to contain viral RNA which is transferred to and expressed in the infected cell. I could further demonstrate that these packaged transcripts exert important biological functions in the infected cells by triggering the initial viral transcription program or acting as immune modulators. In sum, delivered RNAs apparently create a supportive environment that promotes virus establishment in infected B cells. Thus, despite EBV’s classification as a DNA virus, also packaged RNAs are apparently essential for its infectious nature.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: EBV, Herpesvirus, immune response, IL-10, BNLF2a, early phase of infection, pre-latent phase
• Themengebiete: 500 Naturwissenschaften und Mathematik ; 500 Naturwissenschaften und Mathematik > 540 Chemie
• Fakultäten: Fakultät für Chemie und Pharmazie
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 16. Dezember 2011
• 1. Bericht­erstatter:in: Hammerschmidt, Wolfgang