TY - JOUR
T1 - A molecular mechanism for probabilistic bet hedging and its role in viral latency
AU - Chaturvedi, Sonali
AU - Klein, Jonathan
AU - Vardi, Noam
AU - Bolovan-Fritts, Cynthia
AU - Wolf, Marie
AU - Du, Kelvin
AU - Mlera, Luwanika
AU - Calvert, Meredith
AU - Moorman, Nathaniel J.
AU - Goodrum, Felicia
AU - Huang, Bo
AU - Weinberger, Leor S.
N1 - Funding Information:
ACKNOWLEDGMENTS. We thank Edward Mocarski for generously providing us with pp150 expression plasmid and Thomas Stamminger for the generous contribution of the pp71-YFP reporter virus. We thank Elena Ingerman, Melanie Ott, JJ Miranda, Marielle Cavrois, Nandhini Raman, Elizabeth Tanner, Nadia Roan, Jason Neidleman and the L.S.W. laboratory for discussions and suggestions; Melissa Teng and Jinny Wong for technical support; and Kathryn Claiborn for reviewing the manuscript. We acknowledge the Gladstone Flow Cytometry Core, funded through NIH Grant P30 AI027763. S.C. was supported in part by generous donations to the C.B.-F. Memorial Fund. We acknowledge M. Ghassemian at the University of California at San Diego for technical support. L.S.W. acknowledges support from the Bowes Distinguished Professorship, the Alfred P. Sloan Research Fellowship, and NIH Director’s New Innovator Award OD006677 and Pioneer Award OD17181 programs.
Funding Information:
We thank Edward Mocarski for generously providing us with pp150 expression plasmid and Thomas Stamminger for the generous contribution of the pp71-YFP reporter virus. We thank Elena Ingerman, Melanie Ott, JJ Miranda, Marielle Cavrois, Nandhini Raman, Elizabeth Tanner, Nadia Roan, Jason Neidleman and the L.S.W. laboratory for discussions and suggestions; Melissa Teng and Jinny Wong for technical support; and Kathryn Claiborn for reviewing the manuscript. We acknowledge the Gladstone Flow Cytometry Core, funded through NIH Grant P30 AI027763. S.C. was supported in part by generous donations to the C.B.-F. Memorial Fund. We acknowledge M. Ghassemian at the University of California at San Diego for technical support. L.S.W. acknowledges support from the Bowes Distinguished Professorship, the Alfred P. Sloan Research Fellowship, and NIH Director's New Innovator Award OD006677 and Pioneer Award OD17181 programs.
Publisher Copyright:
© 2020 National Academy of Sciences. All rights reserved.
PY - 2020/7/21
Y1 - 2020/7/21
N2 - Probabilistic bet hedging, a strategy to maximize fitness in unpredictable environments by matching phenotypic variability to environmental variability, is theorized to account for the evolution of various fate-specification decisions, including viral latency. However, the molecular mechanisms underlying bet hedging remain unclear. Here, we report that large variability in protein abundance within individual herpesvirus virion particles enables probabilistic bet hedging between viral replication and latency. Superresolution imaging of individual virions of the human herpesvirus cytomegalovirus (CMV) showed that virion-to-virion levels of pp71 tegument protein-the major viral transactivator protein-exhibit extreme variability. This super-Poissonian tegument variability promoted alternate replicative strategies: high virion pp71 levels enhance viral replicative fitness but, strikingly, impede silencing, whereas low virion pp71 levels reduce fitness but promote silencing. Overall, the results indicate that stochastic tegument packaging provides a mechanism enabling probabilistic bet hedging between viral replication and latency.
AB - Probabilistic bet hedging, a strategy to maximize fitness in unpredictable environments by matching phenotypic variability to environmental variability, is theorized to account for the evolution of various fate-specification decisions, including viral latency. However, the molecular mechanisms underlying bet hedging remain unclear. Here, we report that large variability in protein abundance within individual herpesvirus virion particles enables probabilistic bet hedging between viral replication and latency. Superresolution imaging of individual virions of the human herpesvirus cytomegalovirus (CMV) showed that virion-to-virion levels of pp71 tegument protein-the major viral transactivator protein-exhibit extreme variability. This super-Poissonian tegument variability promoted alternate replicative strategies: high virion pp71 levels enhance viral replicative fitness but, strikingly, impede silencing, whereas low virion pp71 levels reduce fitness but promote silencing. Overall, the results indicate that stochastic tegument packaging provides a mechanism enabling probabilistic bet hedging between viral replication and latency.
KW - Fate selection
KW - Herpesvirus
KW - Latency
KW - Stochastic variability
KW - Tegument
UR - http://www.scopus.com/inward/record.url?scp=85088879752&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85088879752&partnerID=8YFLogxK
U2 - 10.1073/pnas.1914430117
DO - 10.1073/pnas.1914430117
M3 - Article
C2 - 32632017
AN - SCOPUS:85088879752
SN - 0027-8424
VL - 117
SP - 17240
EP - 17248
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 29
ER -