Journal article
A gammaherpesvirus Bcl-2 ortholog blocks B cell receptor-mediated apoptosis and promotes the survival of developing B cells in vivo
PLoS pathogens, Vol.10(2), pp.e1003916-e1003916
02/2014
DOI: 10.1371/journal.ppat.1003916
PMCID: PMC3916410
PMID: 24516386
Abstract
Gammaherpesviruses such as Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV, HHV-8) establish lifelong latency in their hosts and are associated with the development of several types of malignancies, including a subset of B cell lymphomas. These viruses are thought to co-opt the process of B cell differentiation to latently infect a fraction of circulating memory B cells, resulting in the establishment of a stable latency setpoint. However, little is known about how this infected memory B cell compartment is maintained throughout the life of the host. We have previously demonstrated that immature and transitional B cells are long-term latency reservoirs for murine gammaherpesvirus 68 (MHV68), suggesting that infection of developing B cells contributes to the maintenance of lifelong latency. During hematopoiesis, immature and transitional B cells are subject to B cell receptor (BCR)-mediated negative selection, which results in the clonal deletion of autoreactive B cells. Interestingly, numerous gammaherpesviruses encode homologs of the anti-apoptotic protein Bcl-2, suggesting that virus inhibition of apoptosis could subvert clonal deletion. To test this, we quantified latency establishment in mice inoculated with MHV68 vBcl-2 mutants. vBcl-2 mutant viruses displayed a marked decrease in the frequency of immature and transitional B cells harboring viral genome, but this attenuation could be rescued by increased host Bcl-2 expression. Conversely, vBcl-2 mutant virus latency in early B cells and mature B cells, which are not targets of negative selection, was remarkably similar to wild-type virus. Finally, in vivo depletion of developing B cells during chronic infection resulted in decreased mature B cell latency, demonstrating a key role for developing B cells in the maintenance of lifelong latency. Collectively, these findings support a model in which gammaherpesvirus latency in circulating mature B cells is sustained in part through the recurrent infection and vBcl-2-mediated survival of developing B cells.
Details
- Title: Subtitle
- A gammaherpesvirus Bcl-2 ortholog blocks B cell receptor-mediated apoptosis and promotes the survival of developing B cells in vivo
- Creators
- Carrie B Coleman - Department of Molecular Genetics & Microbiology and UF Shands Cancer Center, College of Medicine, University of Florida, Gainesville, Florida, United States of AmericaJennifer E McGraw - Department of Molecular Genetics & Microbiology and UF Shands Cancer Center, College of Medicine, University of Florida, Gainesville, Florida, United States of AmericaEmily R Feldman - Department of Molecular Genetics & Microbiology and UF Shands Cancer Center, College of Medicine, University of Florida, Gainesville, Florida, United States of AmericaAlexa N Roth - Department of Molecular Genetics & Microbiology and UF Shands Cancer Center, College of Medicine, University of Florida, Gainesville, Florida, United States of AmericaLisa R Keyes - Department of Molecular Genetics & Microbiology and UF Shands Cancer Center, College of Medicine, University of Florida, Gainesville, Florida, United States of AmericaKatrina R Grau - Department of Molecular Genetics & Microbiology and UF Shands Cancer Center, College of Medicine, University of Florida, Gainesville, Florida, United States of AmericaStephanie L Cochran - Department of Molecular Genetics & Microbiology and UF Shands Cancer Center, College of Medicine, University of Florida, Gainesville, Florida, United States of AmericaThomas J Waldschmidt - Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of AmericaChengyu Liang - Department of Molecular Microbiology & Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of AmericaJ Craig Forrest - Department of Microbiology & Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of AmericaScott A Tibbetts - Department of Molecular Genetics & Microbiology and UF Shands Cancer Center, College of Medicine, University of Florida, Gainesville, Florida, United States of America
- Resource Type
- Journal article
- Publication Details
- PLoS pathogens, Vol.10(2), pp.e1003916-e1003916
- DOI
- 10.1371/journal.ppat.1003916
- PMID
- 24516386
- PMCID
- PMC3916410
- NLM abbreviation
- PLoS Pathog
- ISSN
- 1553-7366
- eISSN
- 1553-7374
- Publisher
- Public Library of Science; United States
- Grant note
- R01 CA140964 / NCI NIH HHS P20-RR018724 / NCRR NIH HHS P20 RR018724 / NCRR NIH HHS P20 GM103625 / NIGMS NIH HHS
- Language
- English
- Date published
- 02/2014
- Academic Unit
- Pathology
- Record Identifier
- 9984046929402771
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