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The speed-fidelity trade-off in influenza A virus evolution

Award Number: F31AI203625
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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The speed-fidelity trade-off in influenza A virus evolution - PROJECT ABSTRACT Influenza A virus (IAV) can mutate rapidly and has a large zoonotic reservoir, leading to a high pandemic potential despite available vaccines and antivirals. The influenza A virus polymerase complex is one of the most important mediators of adaptation and long-term evolution. The error-prone polymerase complex can enable zoonotic leaps and generate mutations that give rise to new antigenic variants. Although it has been suggested that high mutation rates benefit the virus, more recent research indicates that a high mutation rate imposes a constraint on viral evolution. The long-term goal of this proposal is to explore the role of the speed-fidelity trade-off in the evolution of the IAV polymerase complex and how this impacts virus adaptation. The objective of this proposal is to better define the evolutionary forces acting on the IAV polymerase complex and how they alter the evolutionary potential of IAV. The central hypothesis is that the evolution of the IAV polymerase is constrained by its high mutation rate. This hypothesis is based on preliminary data that shows there is an increase in replicative speed over time and that this increase is negatively correlated with replicative fitness. Guided by prior literature and preliminary data, this hypothesis will be tested with two specific aims: 1) define variation in replication speed and fidelity over the course of 50 years of H3N2 evolution and 2) measure the impacts of mutagenic drug treatment on nearly all amino acid substitutions in the influenza RdRP, PB1. In the first aim, a fluorescence-based fluctuation assay will be used to measure mutation rate across all twelve mutational classes, and a competition assay will be used to measure fitness. The second aim will use deep mutational scanning combined with mutagenic drugs to identify amino acid substitutions that lead to high or low fidelity variants. This approach is innovative because it integrates a number of advanced techniques with H3N2 strains isolated over a 50-year period to study the natural course of H3N2 evolution. The proposed research is significant, because it will advance and expand understanding of how the speed-fidelity trade-off impacts influenza A polymerase complex evolution. Ultimately, this knowledge has the potential to inform vaccine design and antiviral drug development. Together with a training plan focused on science communication and honing of research skills, this project will foster the scientific and career development of the applicant.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $50,114 )
2026	2026	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Allergy and Infectious Diseases Research	001	1	7/24/2026	NEW	$0
2026	2026	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Allergy and Infectious Diseases Research	000	1	7/24/2026	NEW	$50,114
														Subtotal = $50,114

Grand Total All Awards = $50,114

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The speed-fidelity trade-off in influenza A virus evolution

Award Number: F31AI203625

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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