The Role of Toll-like Receptor Signaling During theEstablishment of and Reactivation from Murine Gammaherpesvirus 68Latency Open Access
Gargano, Lisa (2009)
Abstract
The Role of Toll-like Receptor Signaling During the Establishment of and Reactivation from Murine Gammaherpesvirus 68 Latency By Lisa Marie Gargano Murine gammaherpesvirus 68 (MHV68) establishes a life-long infection in mice and is used as a model system to study the role of viral and host factors in chronic infections. Long-term persistence depends on the ability of MHV68 to establish latency and reactivate from latency to reseed new latency reservoirs. Toll-like receptor (TLR) signaling plays an essential role in the activation of innate immunity by recognizing specific patterns of microbial components. In the first aim, I investigated the role of TLR signaling in MHV68 latency in vivo. I found that unlike in TLR3-/- mice, B-cells from MyD88-/- mice displayed a decrease in the frequency of activated, germinal center and class switched B-cells. While acute virus replication in the lungs was unaffected, establishment of latency was decreased in MyD88-/- mice. In mixed bone-marrow chimeric mice, there was a selective failure of the MyD88-/- B-cells to undergo an optimal response. While MHV68 established latency efficiently in the MyD88+/+ B-cells, there was a reduction in the frequency of MyD88-/- B-cells harboring latent MHV68. This data supports a model whereby establishment of gammaherpesvirus latency is dependent upon the virus gaining access to the memory B-cell reservoir. In the second aim I investigated the ability of TLR ligands to induce MHV68 reactivation. I found that stimulation of a latently infected B-cell line with TLR ligands enhanced MHV68 reactivation. Ex vivo stimulation of latently infected splenocytes with TLR ligands led to early B-cell activation and proliferation with a concomitant increase in MHV68 reactivation. When LPS or CpG was administered in vivo there was an increase in B-cell activation and MHV68 reactivation and also an increase in the CD8+ T-cell response. MHV68 reactivation leads to an increase of viral genome positive cells at 14 days post-stimulation. These data suggest that control of gammaherpesvirus latency might be disrupted upon TLR signaling in response to subsequent pathogens in vivo. Together findings demonstrate a critical role of TLR signaling during MHV68 infection.
Table of Contents
2 TABLE OF CONTENTS Abstract Cover Page Abstract Cover Page Acknowledgements Table of Contents List of Figures and Tables Chapter I: Introduction 1 Figures 12 Figure Legends 15 Chapter II: Role of MyD88 Signaling in Murine Gammaherpesvirus 68 Latency 16 Introduction 18 Materials and Methods 21 Results B cells in MyD88-/- mice display a decrease in response 28 Development of an antibody response to MHV68 is delayed 29 in MyD88-/- mice TLR signaling is dispensable for MHV68 acute replication 31 in vivo Loss of MyD88 signaling results in route of inoculation 31 specific defects in MHV68 latency Inhibition of NF-B signaling in MHV68 infected MyD88-/- 33 mice leads to a further reduction in viral latency MyD88-/-/MyD88+/+ mixed bone marrow chimeric mice are 34 able to control acute MHV68 replication, but MyD88-/- B cells in these mice retain the defects in B cell differentiation and establishment of MHV68 latency Discussion 37 Acknowledgements 43 Figures and Tables 44 Figure Legends 55
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