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Viruses and Burgers : = Exploring the Role of Lipoproteins & Lipoprotein Receptors in Gammaherpesvirus Infection.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Viruses and Burgers :/
Reminder of title:	Exploring the Role of Lipoproteins & Lipoprotein Receptors in Gammaherpesvirus Infection.
Author:	Aurubin, Carlie Anne.
Description:	1 online resource (163 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 83-01, Section: B.
Contained By:	Dissertations Abstracts International83-01B.
Subject:	Virology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=28493619click for full text (PQDT)
ISBN:	9798516081309

Viruses and Burgers : = Exploring the Role of Lipoproteins & Lipoprotein Receptors in Gammaherpesvirus Infection.
Aurubin, Carlie Anne.

Viruses and Burgers :Exploring the Role of Lipoproteins & Lipoprotein Receptors in Gammaherpesvirus Infection. - 1 online resource (163 pages)

Source: Dissertations Abstracts International, Volume: 83-01, Section: B.

Thesis (Ph.D.)--The Medical College of Wisconsin, 2021.

Includes bibliographical references

Gammaherpesviruses infect 95% of the human population. Infection lasts for the entire lifetime of the host and can be associated with several cancers. Despite the high prevalence, there is minimal understanding of how these viruses drive tumorigenesis. Recently, it has come to light that gammaherpesviruses impacts lipid synthesis to facilitate infection. We showed that endogenous cholesterol synthesis supports gammaherpesvirus replication. However, the role of exogenous cholesterol exchange and signaling during infection has not been addressed and remains a significant knowledge gap considering a high prevalence of both gammaherpesvirus infection and hypercholesterolemia. The two human gammaherpesviruses are Epstein-Barr Virus (EBV) and Kaposi's Sarcoma Associated herpesvirus (KSHV). These viruses are highly species-specific, which significantly limits the scope of EBV and KSHV studies. To overcome this limitation, murine gammaherpesvirus 68 (MHV68) is utilized in our studies. MHV68 is genetically and biologically related to KSHV and EBV and is a tractable experimental model for the study of gammaherpesvirus pathogenesis.The exogenous cholesterol transport utilizes lipoproteins, high-density lipoproteins (HDL), and low-density lipoproteins (LDL) to transport cholesterol in circulation due to cholesterol's insolubility in serum. A protein component, called apolipoprotein, is embedded in lipoproteins and functions as ligands for lipoprotein receptors. LDL particles engage the LDL receptor (LDL-R) to facilitate internalization, providing cholesterol to fuel cellular function. Scavenger Receptor Class B Type I (SR-BI) binds HDL particles, enabling the removal of excess cellular cholesterol for hepatobiliary clearance or recycling. Apolipoprotein E (ApoE) functions as a surface ligand on several lipoproteins and facilitates lipoprotein engagement with lipoprotein receptors. We found that LDL-R expression attenuates gammaherpesvirus replication during the early stages of the replication cycle, as evident by increased viral titers and viral gene expression in LDL-R-/- primary macrophages. This exaggerated viral replication stems from LDL-R-dependent alterations in the endogenous cholesterol synthesis pathway. Specifically, LDL-R suppresses endogenous cholesterol synthesis, limiting MHV68 access to this pro-viral pathway. Deletion of LDL-R did not alter gammaherpesvirus latency or reactivation in mice. Yet, BL6 and LDL-R-/- mice placement on a hypercholesterolemic Western diet attenuates MHV68 splenic reactivation. Intriguingly, neither diet nor genetically-induced hypercholesterolemia alters the adaptive immune response to MHV68. We found that SR-BI supports MHV68 replication and suppresses Type I IFN response in primary macrophages. Ironically, HDL, the ligand for SR-BI, had differing effects, instead attenuating MHV68 gene expression. Yet, the anti-viral effect of HDL on MHV68 viral gene expression did not correlate with HDL effects on MHV68 replication. HDL supports MHV68 replication in a time-dependent manner. In vivo, SR-BI supports MHV68 reactivation but not latency in spleens of chronically infected mice. Like LDL-R, SR-BI does not alter MHV68-driven immune response. MHV68 infection induces ApoE mRNA expression in primary macrophages in a type I interferon-dependent manner. Yet, ApoE is dispensable in MHV68 replication. In vivo, ApoE supports MHV68 latency and reactivation in chronically infected mice. Overall, our studies demonstrates that lipoproteins, their receptors, and components exert differential effects on infection through a complex network of interactions between metabolic and immune pathways of the host, revealing an insight into the regulation of gammaherpesvirus infection by cholesterol metabolism. Defining this interplay is likely to offer a unique perspective on gammaherpesvirus infection and lymphomagenesis.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2023

Mode of access: World Wide Web

ISBN: 9798516081309Subjects--Topical Terms:

642304
Virology.
Subjects--Index Terms:

GammaherpesvirusesIndex Terms--Genre/Form:

542853
Electronic books.

Viruses and Burgers : = Exploring the Role of Lipoproteins & Lipoprotein Receptors in Gammaherpesvirus Infection.
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520 $a Gammaherpesviruses infect 95% of the human population. Infection lasts for the entire lifetime of the host and can be associated with several cancers. Despite the high prevalence, there is minimal understanding of how these viruses drive tumorigenesis. Recently, it has come to light that gammaherpesviruses impacts lipid synthesis to facilitate infection. We showed that endogenous cholesterol synthesis supports gammaherpesvirus replication. However, the role of exogenous cholesterol exchange and signaling during infection has not been addressed and remains a significant knowledge gap considering a high prevalence of both gammaherpesvirus infection and hypercholesterolemia. The two human gammaherpesviruses are Epstein-Barr Virus (EBV) and Kaposi's Sarcoma Associated herpesvirus (KSHV). These viruses are highly species-specific, which significantly limits the scope of EBV and KSHV studies. To overcome this limitation, murine gammaherpesvirus 68 (MHV68) is utilized in our studies. MHV68 is genetically and biologically related to KSHV and EBV and is a tractable experimental model for the study of gammaherpesvirus pathogenesis.The exogenous cholesterol transport utilizes lipoproteins, high-density lipoproteins (HDL), and low-density lipoproteins (LDL) to transport cholesterol in circulation due to cholesterol's insolubility in serum. A protein component, called apolipoprotein, is embedded in lipoproteins and functions as ligands for lipoprotein receptors. LDL particles engage the LDL receptor (LDL-R) to facilitate internalization, providing cholesterol to fuel cellular function. Scavenger Receptor Class B Type I (SR-BI) binds HDL particles, enabling the removal of excess cellular cholesterol for hepatobiliary clearance or recycling. Apolipoprotein E (ApoE) functions as a surface ligand on several lipoproteins and facilitates lipoprotein engagement with lipoprotein receptors. We found that LDL-R expression attenuates gammaherpesvirus replication during the early stages of the replication cycle, as evident by increased viral titers and viral gene expression in LDL-R-/- primary macrophages. This exaggerated viral replication stems from LDL-R-dependent alterations in the endogenous cholesterol synthesis pathway. Specifically, LDL-R suppresses endogenous cholesterol synthesis, limiting MHV68 access to this pro-viral pathway. Deletion of LDL-R did not alter gammaherpesvirus latency or reactivation in mice. Yet, BL6 and LDL-R-/- mice placement on a hypercholesterolemic Western diet attenuates MHV68 splenic reactivation. Intriguingly, neither diet nor genetically-induced hypercholesterolemia alters the adaptive immune response to MHV68. We found that SR-BI supports MHV68 replication and suppresses Type I IFN response in primary macrophages. Ironically, HDL, the ligand for SR-BI, had differing effects, instead attenuating MHV68 gene expression. Yet, the anti-viral effect of HDL on MHV68 viral gene expression did not correlate with HDL effects on MHV68 replication. HDL supports MHV68 replication in a time-dependent manner. In vivo, SR-BI supports MHV68 reactivation but not latency in spleens of chronically infected mice. Like LDL-R, SR-BI does not alter MHV68-driven immune response. MHV68 infection induces ApoE mRNA expression in primary macrophages in a type I interferon-dependent manner. Yet, ApoE is dispensable in MHV68 replication. In vivo, ApoE supports MHV68 latency and reactivation in chronically infected mice. Overall, our studies demonstrates that lipoproteins, their receptors, and components exert differential effects on infection through a complex network of interactions between metabolic and immune pathways of the host, revealing an insight into the regulation of gammaherpesvirus infection by cholesterol metabolism. Defining this interplay is likely to offer a unique perspective on gammaherpesvirus infection and lymphomagenesis.
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