Influenza viruses, commonly called flu, can evade our immune system and develop resistance to treatments by changing frequently. Specifically, mutations in their genome cause influenza proteins to change in ways that can help the virus evade our defences. However, these mutations come at a cost and can prevent the viral proteins from forming functional and stable three-dimensional shapes – a process known as protein folding – thereby hampering the virus’ ability to replicate. In human cells, proteins called chaperones can help our other proteins fold properly. Influenza viruses do not have their own chaperones and, instead, hijack those of their host. Host chaperones are therefore crucial to the virus’ ability to replicate. However, until now, it was not known if host chaperones can influence how these viruses evolve. Here, Phillips et al. used mammalian cells to study how host chaperones affect an evolving influenza population. First, cells were engineered to either have normal chaperone levels, elevated chaperone levels, or inactive chaperones. Next, the H3N2 influenza strain was grown in these different conditions for nearly 200 generations and sequenced to determine how the virus evolved in each distinctive host chaperone environment. Phillips et al. discovered that host chaperones affect the rate at which mutations accumulate in the influenza population, and also the types of mutations in the influenza genome. For instance, when a chaperone called Hsp90 was inactivated, mutations became prevalent in the viral population more slowly than in cells with normal or elevated chaperone levels. Moreover, some specific mutations fared better in cells with high chaperone levels, whilst others worked better in cells with inactivated chaperones. These results suggest that influenza evolution is affected by host chaperone levels in complex and important ways. Moreover, whether chaperones will promote or hinder the effects of any single mutation is difficult to predict ahead of time. This discovery is significant, as the chaperones available to influenza can vary in different tissues, organisms and infectious conditions, and may therefore influence the virus' ability to change and evolve in a context-specific manner. The findings are likely to extend to other viruses such as HIV and Ebola, which also hijack host chaperones for the same purpose. More work is now needed to systematically quantify these effects so that we can better predict how specific chaperones will affect the ability of viruses to adapt, especially in pathologically relevant conditions like fever or viral host-switching. In the future, such insights could help shape the design of treatments to which viruses do not evolve resistance.
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Bacterial Hsp90 predominantly buffers but does not potentiate the phenotypic effects of deleterious mutations during fluorescent protein evolution
Chaperones facilitate the folding of other (“client”) proteins and can thus affect the adaptive evolution of these clients. Specifically, chaperones affect the phenotype of proteins via two opposing mechanisms. On the one hand, they can buffer the effects of mutations in proteins and thus help preserve an ancestral, premutation phenotype. On the other hand, they can potentiate the effects of mutations and thus enhance the phenotypic changes caused by a mutation. We study that how the bacterial Hsp90 chaperone (HtpG) affects the evolution of green fluorescent protein. To this end, we performed directed evolution of green fluorescent protein under low and high cellular concentrations of Hsp90. Specifically, we evolved green fluorescent protein under both stabilizing selection for its ancestral (green) phenotype and directional selection toward a new (cyan) phenotype. While Hsp90 did only affect the rate of adaptive evolution transiently, it did affect the phenotypic effects of mutations that occurred during adaptive evolution. Specifically, Hsp90 allowed strongly deleterious mutations to accumulate in evolving populations by buffering their effects. Our observations show that the role of a chaperone for adaptive evolution depends on the organism and the trait being studied.
more » « less- NSF-PAR ID:
- 10383160
- Publisher / Repository:
- Oxford University Press
- Date Published:
- Journal Name:
- Genetics
- Volume:
- 222
- Issue:
- 4
- ISSN:
- 1943-2631
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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