Globally defining the effects of mutations in a picornavirus capsid.
Elife
; 102021 01 12.
Article
in En
| MEDLINE
| ID: mdl-33432927
ABSTRACT
The capsids of non-enveloped viruses are highly multimeric and multifunctional protein assemblies that play key roles in viral biology and pathogenesis. Despite their importance, a comprehensive understanding of how mutations affect viral fitness across different structural and functional attributes of the capsid is lacking. To address this limitation, we globally define the effects of mutations across the capsid of a human picornavirus. Using this resource, we identify structural and sequence determinants that accurately predict mutational fitness effects, refine evolutionary analyses, and define the sequence specificity of key capsid-encoded motifs. Furthermore, capitalizing on the derived sequence requirements for capsid-encoded protease cleavage sites, we implement a bioinformatic approach for identifying novel host proteins targeted by viral proteases. Our findings represent the most comprehensive investigation of mutational fitness effects in a picornavirus capsid to date and illuminate important aspects of viral biology, evolution, and host interactions.
A virus is made up of genetic material that is encased with a protective protein coat called the capsid. The capsid also helps the virus to infect host cells by binding to the host receptor proteins and releasing its genetic material. Inside the cell, the virus hitchhikes the infected cell's machinery to grow or replicate its own genetic material. Viral capsids are the main target of the host's defence system, and therefore, continuously change in an attempt to escape the immune system by introducing alterations (known as mutations) into the genes encoding viral capsid proteins. Mutations occur randomly, and so while some changes to the viral capsid might confer an advantage, others may have no effect at all, or even weaken the virus. To better understand the effect of capsid mutations on the virus' ability to infect host cells, Mattenberger et al. studied the Coxsackievirus B3, which is linked to heart problems and acute heart failure in humans. The researchers analysed around 90% of possible amino acid mutations (over 14,800 mutations) and correlated each mutation to how it influenced the virus' ability to replicate in human cells grown in the laboratory. Based on these results, Mattenberger et al. developed a computer model to predict how a particular mutation might affect the virus. The analysis also identified specific amino acid sequences of capsid proteins that are essential for certain tasks, such as building the capsid. It also included an analysis of sequences in the capsid that allow it to be recognized by another viral protein, which cuts the capsid proteins into the right size from a larger precursor. By looking for similar sequences in human genes, the researchers identified several ones that the virus may attack and inactivate to support its own replication. These findings may help identify potential drug targets to develop new antiviral therapies. For example, proteins of the capsid that are less likely to mutate will provide a better target as they lower the possibility of the virus to become resistant to the treatment. They also highlight new proteins in human cells that could potentially block the virus in cells.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Picornaviridae
/
Capsid
/
Capsid Proteins
/
Mutation
Type of study:
Prognostic_studies
Language:
En
Journal:
Elife
Year:
2021
Document type:
Article
Affiliation country:
Spain
Country of publication:
ENGLAND
/
ESCOCIA
/
GB
/
GREAT BRITAIN
/
INGLATERRA
/
REINO UNIDO
/
SCOTLAND
/
UK
/
UNITED KINGDOM