Globally defining the effects of mutations in a picornavirus capsid

ABSTRACTThe capsids of non-enveloped viruses are highly multimeric and multifunctional protein assemblies that protect the viral genome between infection cycles, dictate host and cell tropism, and mediate evasion of humoral immune responses. As such, capsids 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 in the capsid of a human picornavirus, generating a comprehensive dataset encompassing >90% of all possible single amino acid mutations. Moreover, we use this information to identify structural and sequence determinants that accurately predict mutational fitness effects, refine evolutionary analyses, and define the sequence specificity of key capsid encoded motifs. Finally, capitalizing on the sequence requirements identified in our dataset for capsid encoded protease cleavage sites, we implement and validate a bioinformatic approach for identifying novel host proteins targeted by viral proteases. Our findings present 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.

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Globally defining the effects of mutations in a picornavirus capsid

eLife ◽

10.7554/elife.64256 ◽

2021 ◽

Vol 10 ◽

Author(s):

Florian Mattenberger ◽

Victor Latorre ◽

Omer Tirosh ◽

Adi Stern ◽

Ron Geller

Keyword(s):

Viral Fitness ◽

Sequence Specificity ◽

Protein Assemblies ◽

Multifunctional Protein ◽

Host Interactions ◽

Fitness Effects ◽

Protease Cleavage ◽

Viral Proteases ◽

Novel Host ◽

Protease Cleavage Sites

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.

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Deep mutational scanning of hemagglutinin helps predict evolutionary fates of human H3N2 influenza variants

10.1101/298364 ◽

2018 ◽

Cited By ~ 7

Author(s):

Juhye M. Lee ◽

John Huddleston ◽

Michael B. Doud ◽

Kathryn A. Hooper ◽

Nicholas C. Wu ◽

...

Keyword(s):

Cell Culture ◽

Influenza Virus ◽

Amino Acid ◽

Virus Evolution ◽

Viral Fitness ◽

Single Amino Acid ◽

Similar Data ◽

Viral Growth ◽

Amino Acid Mutations ◽

H3n2 Influenza

Human influenza virus rapidly accumulates mutations in its major surface protein hemagglutinin (HA). The evolutionary success of influenza virus lineages depends on how these mutations affect HA’s functionality and antigenicity. Here we experimentally measure the effects on viral growth in cell culture of all single amino-acid mutations to the HA from a recent human H3N2 influenza virus strain. We show that mutations that are measured to be more favorable for viral growth are enriched in evolutionarily successful H3N2 viral lineages relative to mutations that are measured to be less favorable for viral growth. Therefore, despite the well-known caveats about cell-culture measurements of viral fitness, such measurements can still be informative for understanding evolution in nature. We also compare our measurements for H3 HA to similar data previously generated for a distantly related H1 HA, and find substantial differences in which amino acids are preferred at many sites. For instance, the H3 HA has less disparity in mutational tolerance between the head and stalk domains than the H1 HA. Overall, our work suggests that experimental measurements of mutational effects can be leveraged to help understand the evolutionary fates of viral lineages in nature — but only when the measurements are made on a viral strain similar to the ones being studied in nature.Significance StatementA key goal in the study of influenza virus evolution is to forecast which viral strains will persist and which ones will die out. Here we experimentally measure the effects of all amino-acid mutations to the hemagglutinin protein from a human H3N2 influenza strain on viral growth in cell culture. We show that these measurements have utility for distinguishing among viral strains that do and do not succeed in nature. Overall, our work suggests that new high-throughput experimental approaches may be useful for understanding virus evolution in nature.

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Adaptive potential of a drug-targeted viral protein as a function of environmental stress

10.1101/078428 ◽

2016 ◽

Cited By ~ 1

Author(s):

Lei Dai ◽

Yushen Du ◽

Hangfei Qi ◽

Christian D. Huber ◽

Nicholas C. Wu ◽

...

Keyword(s):

Environmental Stress ◽

Rna Viruses ◽

Geometric Model ◽

Antiviral Drug ◽

Viral Fitness ◽

Single Amino Acid ◽

Adaptive Potential ◽

Beneficial Mutations ◽

Fitness Effects ◽

Ns5a Protein

AbstractRNA viruses are notorious for their ability to evolve rapidly under selection in novel environments. It is known that the high mutation rate of RNA viruses can generate huge genetic diversity to facilitate viral adaptation. However, less attention has been paid to the underlying fitness landscape that represents the selection forces on viral genomes. Here we systematically quantified the distribution of fitness effects (DFE) of about 1,600 single amino acid substitutions in the drug-targeted region of NS5A protein of Hepatitis C Virus (HCV). We found that the majority of non-synonymous substitutions incur large fitness costs, suggesting that NS5A protein is highly optimized in natural conditions. We characterized the adaptive potential of HCV by subjecting the mutant viruses to selection by the antiviral drug Daclatasvir. Both the selection coefficient and the number of beneficial mutations are found to increase with the level of environmental stress, which is modulated by the concentration of Daclatasvir. The changes in the spectrum of beneficial mutations in NS5A protein can be explained by a pharmacodynamics model describing viral fitness as a function of drug concentration. We test theoretical predictions regarding the distribution of beneficial fitness effects of mutations. We also interpret the data in the context of Fisher’s Geometric Model and find an increased distance to optimum as a function of environmental stress. Finally, we show that replication fitness of viruses is correlated with the pattern of sequence conservation in nature and viral evolution is constrained by the need to maintain protein stability.

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Specific humoral immune responses in 12 cases of food sensitization to sesame seed

Clinical & Experimental Allergy ◽

10.1046/j.1365-2222.1997.1490951.x ◽

1997 ◽

Vol 27 (11) ◽

pp. 1285-1291 ◽

Cited By ~ 2

Author(s):

M. N. KOLOPP-SARDA ◽

D. A. MONERET-VAUTRIN ◽

B. GOBERT ◽

G. KANNY ◽

M. BRODSCHII ◽

...

Keyword(s):

Immune Responses ◽

Sesame Seed ◽

Humoral Immune ◽

Humoral Immune Responses ◽

Food Sensitization

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Faculty Opinions recommendation of Comparative ability of plasmid IL-12 and IL-15 to enhance cellular and humoral immune responses elicited by a SIVgag plasmid DNA vaccine and alter disease progression following SHIV(89.6P) challenge in rhesus macaques.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1079898.532828 ◽

2007 ◽

Author(s):

Michael Keefer

Keyword(s):

Immune Responses ◽

Disease Progression ◽

Dna Vaccine ◽

Plasmid Dna ◽

Rhesus Macaques ◽

Humoral Immune ◽

Humoral Immune Responses ◽

Plasmid Dna Vaccine

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Faculty Opinions recommendation of Critical role of the IgM Fc receptor in IgM homeostasis, B-cell survival, and humoral immune responses.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717959020.793462522 ◽

2012 ◽

Author(s):

Takeshi Tsubata

Keyword(s):

Immune Responses ◽

B Cell ◽

Cell Survival ◽

Critical Role ◽

Fc Receptor ◽

Humoral Immune ◽

Humoral Immune Responses ◽

B Cell Survival

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Faculty of 1000 evaluation for Head-to-head comparison of humoral immune responses to Vi capsular polysaccharide and Salmonella Typhi Ty21a typhoid vaccines--a randomized trial.

F1000 - Post-publication peer review of the biomedical literature ◽

10.3410/f.718006642.793478204 ◽

2013 ◽

Author(s):

David Murdoch ◽

Gary McAuliffe

Keyword(s):

Immune Responses ◽

Randomized Trial ◽

Capsular Polysaccharide ◽

Salmonella Typhi ◽

Humoral Immune ◽

Humoral Immune Responses ◽

Vi Capsular Polysaccharide ◽

Typhoid Vaccines

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Production and immunological evaluation of epitope-based preventative pneumococcal candidate vaccine comprising immunodominant epitopes from PspA, CbpA, PhtD and PiuA antigens

Current Pharmaceutical Biotechnology ◽

10.2174/1389201022666201231112029 ◽

2020 ◽

Vol 22 ◽

Author(s):

Hesam Dorosti ◽

Navid Nezafat ◽

Reza Heidari ◽

Mohammad Bagher Ghoshoon ◽

Ahmad Gholami ◽

...

Keyword(s):

T Lymphocytes ◽

Pneumococcal Vaccine ◽

Peptide Vaccine ◽

Promising Alternative ◽

Humoral Immune ◽

Humoral Immune Responses ◽

Serotype Replacement ◽

Tnf Α ◽

Immunological Evaluation ◽

Immunodominant Epitopes

Background: Streptococcus pneumoniae is a leading cause of pneumonia, mostly in children less than five years and elderly people. Although the pneumoniae polysaccharide vaccine (PPV) and pneumonia conjugate vaccines (PCV) are the efficient pneumococcal vaccine in adult and children groups, but the serotype replacement of S. pneumoniae strains causes the reduction in the efficacy of PPV and PCV vaccines. Epitope-based vaccines are a promising alternative to the present capsular antigen vaccines. Methods: In this study, we evaluated cellular and humoral immune responses induced by our novel designed multi-epitope vaccine in BALB/c mice. CD8+ cytolytic T lymphocytes (CTLs) epitopes were selected from PspA and CbpA antigens, and CD4+ helper T lymphocytes (HTLs) epitopes were chosen from PhtD and PiuA antigens. PorB, the TLR2 agonist, as an adjuvant, was employed to increase the immunogenicity of the vaccine. Results and conclusion: The high levels of specific anti-peptide vaccine IgG and an increase in the level of IgG2 in the vaccinated group demonstrated our vaccine could elicit a robust antibody production. The significant increase in IFN-γ, IL-2, TNF-α, IL-4, IL-6, and decrease in IL-10 showed that, the designed vaccine could be proposed as the efficient preventative pneumococcal vaccine in the mouse model.

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