Variation in influenza virus neuraminidase activity influences the evolutionary trajectory of hemagglutinin

Antigenic evolution of the influenza A virus (IAV) hemagglutinin (HA) gene limits efforts to effectively control the spread of these viruses in the human population through vaccination. Efforts to understand the mechanisms that govern HA antigenic evolution typically ignore the requirement that IAV must maintain a functional balance between HA receptor-binding and the receptor-destroying activity of neuraminidase (NA), which may vary between viral genotypes. We hypothesize that the need to maintain functional balance with NA significantly constrains the evolutionary potential of the HA gene. In Chapter 2, we used deep mutational scanning to show that variation in NA background altered the HA fitness landscape in a lab-adaptive H1N1 strain, lowering NA activity could increase the overall mutational robustness of HA. Specifically, residues involved in receptor binding were more sensitive to the influence of NA. Consistent with this, we observed that different NA backgrounds supported the emergence of distinct repertoires of HA escape variants under neutralizing antibody pressure. In Chapter 3, we focused on changes in NA activity in the circulating seasonal H1N1 lineage and the effect on HA mutational fitness landscape and antibody escape profile. Like what we observed in the lab-adaptive strain, we found that residues around the receptor binding site were more suspectable to the epistatic regulation of NA activity. Given the identical immune pressure from monoclonal antibodies, HA evolved to different mutants in different NA backgrounds. In Chapter 4, we tested the feasibility of using a cell pull-down assay combined with the deep mutational scanning library we generated to assess the HA mutants’ avidity to the receptor in a high-throughput manner. However, the results suffered from a high noise level and low representation of the HA mutants. We were unable to enrich the fast-binding variants in the early time points. We conclude that the method described here is unsuitable for the purpose. In conclusion, we demonstrated the NA activity of influenza A virus is one of the constraints and factors that determine the evolutionary potential and trajectory of HA. Our results highlight the importance of considering epistatic interactions with NA when attempting to predict HA evolution.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Microbiology

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2024

Author dc:creator

• Liu, Tongyu

Contributors dc:contributor

• Brooke, Christopher B.
• Kieffer, Collin D.
• Stadtmueller, Beth M.
• Whitaker, Rachel J.

• Influenza Virus
• Antigenic Evolution
• Epistasis
• Mutational Fitness Landscape
• Ha-na Balance

Statement dc:rights

• Copyright 2024 Tongyu Liu

Language dc:language

en, eng

Handle dc:identifier

https://hdl.handle.net/2142/124522

OAI record oai:identifier

https://www.ideals.illinois.edu/oai-pmh?verb=GetRecord&metadataPrefix=etdms&identifier=oai%3Awww.ideals.illinois.edu%3A2142%2F124522