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Genetic and Metabolic Regulation of Epstein Barr Virus Infection


Engelmann, Christine. Genetic and Metabolic Regulation of Epstein Barr Virus Infection. 2022, University of Zurich, Faculty of Science.

Abstract

Epstein Barr virus is an oncogenic gamma-herpesvirus that infects more than 95% of the human adult population. Besides causing infectious mononucleosis in adolescents and young adults, EBV is associated with a broad spectrum of tumors of lymphoid or epithelial cell origin. In the majority of cases, the immune system of healthy subjects is able to control the virus and prevent overt disease. On the other hand, patients with monogenic mutations leading to primary immunodeficiency disorders (PIDs) are often unable to properly control this oncogenic virus and go on to develop EBV-associated lymphoproliferations.

In the first project of this thesis we investigated the EBV infection in the context of the primary immunodeficiency caused by mutations in the X-linked inhibitor of apoptosis (XIAP) protein. XIAP patients represent a peculiarity among PIDs with susceptibility to EBV as they do not develop EBV-associated tumors. This is surprising due to the compromised T cell survival this mutation causes. XIAP is best known for its regulatory functions of apoptosis by preventing the activation of caspases but is also involved in other signaling pathways, mainly through its function as an E3-ligase. In our humanized mouse model we simulated XIAP-deficiency with small molecules called
SMAC-mimetics and found a reduction in circulating B cells and T cells, an effect even more pronounced upon EBV infection. Additionally, we described four individual XIAP patients who presented with reduced frequencies of memory B cells, suggesting that
XIAP plays a role in B cell maintenance. EBV infection of XIAP-deficient primary B cells resulted in outgrowth of lymphoblastoid cell lines expressing the tumor suppressor CADM1, which, although we couldn’t verify an in vitro effect on survival, might play a
role in vivo.

In the second project described here we evaluated the utility of the MISTRG humanized mouse model for EBV infection to study the role of myeloid-derived suppressor cells and their effector molecule IDO1 during EBV infection. NSG mice develop human myeloid cells to insufficient levels and were thus not suitable to study these cell populations. Even though the MISTRG model allowed for significant higher reconstitution levels of human myeloid cells, they also rapidly developed anemia and were thus unable to support the 5 weeks of EBV infection.

In the last project, we demonstrated the importance of the kynurenine-pathway during primary EBV infection in humanized NSG mice, through blockade of the ratelimiting IDO1 enzyme. IDO1 expression is upregulated in primary B cells during the first days after EBV infection. Viral loads as well as tumorigenesis were significantly reduced in treated mice, suggesting a druggable pathway to prevent EBV infection.

Abstract

Epstein Barr virus is an oncogenic gamma-herpesvirus that infects more than 95% of the human adult population. Besides causing infectious mononucleosis in adolescents and young adults, EBV is associated with a broad spectrum of tumors of lymphoid or epithelial cell origin. In the majority of cases, the immune system of healthy subjects is able to control the virus and prevent overt disease. On the other hand, patients with monogenic mutations leading to primary immunodeficiency disorders (PIDs) are often unable to properly control this oncogenic virus and go on to develop EBV-associated lymphoproliferations.

In the first project of this thesis we investigated the EBV infection in the context of the primary immunodeficiency caused by mutations in the X-linked inhibitor of apoptosis (XIAP) protein. XIAP patients represent a peculiarity among PIDs with susceptibility to EBV as they do not develop EBV-associated tumors. This is surprising due to the compromised T cell survival this mutation causes. XIAP is best known for its regulatory functions of apoptosis by preventing the activation of caspases but is also involved in other signaling pathways, mainly through its function as an E3-ligase. In our humanized mouse model we simulated XIAP-deficiency with small molecules called
SMAC-mimetics and found a reduction in circulating B cells and T cells, an effect even more pronounced upon EBV infection. Additionally, we described four individual XIAP patients who presented with reduced frequencies of memory B cells, suggesting that
XIAP plays a role in B cell maintenance. EBV infection of XIAP-deficient primary B cells resulted in outgrowth of lymphoblastoid cell lines expressing the tumor suppressor CADM1, which, although we couldn’t verify an in vitro effect on survival, might play a
role in vivo.

In the second project described here we evaluated the utility of the MISTRG humanized mouse model for EBV infection to study the role of myeloid-derived suppressor cells and their effector molecule IDO1 during EBV infection. NSG mice develop human myeloid cells to insufficient levels and were thus not suitable to study these cell populations. Even though the MISTRG model allowed for significant higher reconstitution levels of human myeloid cells, they also rapidly developed anemia and were thus unable to support the 5 weeks of EBV infection.

In the last project, we demonstrated the importance of the kynurenine-pathway during primary EBV infection in humanized NSG mice, through blockade of the ratelimiting IDO1 enzyme. IDO1 expression is upregulated in primary B cells during the first days after EBV infection. Viral loads as well as tumorigenesis were significantly reduced in treated mice, suggesting a druggable pathway to prevent EBV infection.

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Additional indexing

Item Type:Dissertation (cumulative)
Referees:Münz Christian, Shannon-Lowe Claire
Communities & Collections:04 Faculty of Medicine > Institute of Experimental Immunology
UZH Dissertations
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:10 May 2022
Deposited On:30 Jan 2023 10:31
Last Modified:30 Jan 2023 10:31
OA Status:Closed
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