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Genetic and biophysical mechanisms that control influenza virus cellular multiplicity of infection

Award Number: R01AI171445
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Genetic and biophysical mechanisms that control influenza virus cellular multiplicity of infection - Single cells infected by influenza can produce hundreds to thousands of infectious new virions. These virions spread non-uniformly, producing wide variations in the viral load per cell that are concentrated around the initial site of infection. Differences in the amount of virus that infects a particular cell can influence whether or not that cell produces new virions of its own, or if it mounts an anti-viral response. Understanding how influenza virions spread is therefore critical to understanding how infection progresses and how the host responds. The central goal of this project is to understand how genetic and biophysical features of both virus and host contribute to the spatial structure of influenza virus cellular spread, and how differences in cellular spread shape the progression of infection and the resulting cellular responses. Our prior data demonstrate that genetic and biophysical features of influenza control the way that the virus spreads at the cellular level. These features are strongly linked to three viral proteins in particular: HA, NA, and M1. The receptor-binding protein HA mediates virus attachment to naïve cells, while the receptor-destroying protein NA facilitates virus release and dissemination. The matrix protein M1 controls the shape of the virus particle and the distribution of HA and NA on the virion surface. Collectively, these proteins control the biophysical characteristics of virus particles and shape the way that virions spread throughout the host. We hypothesize that genetic mechanisms acting through these proteins, together with host factors involved in mucociliary clearance, determine the spatial pattern of viral spread and the frequency of cellular co-infection, thereby shaping the progression of disease. We will test this hypothesis through two specific aims. In Aim 1, we will use high- resolution imaging to track the spread of virions and viral infection, and we will determine how this depends on natural variations in HA, NA, and M1. Through these experiments, we will identify how these proteins collectively influence the degree of cellular co-infection that occurs during multi-cycle virus replication. In Aim 2, we will investigate how host factors involved in mucociliary clearance contribute to cellular spread of IAV, and we will determine the collective impact of viral and host factors that alter the frequency of co-infection on key infection outcomes in differentiated human airway cells. The expected outcome of this project is an improved understanding of how influenza virus surface and structural proteins contribute to intracellular aspects of viral replication by tuning the degree of co-infection that occurs during multi-cycle growth. Insights from this work will inform basic understanding of how influenza viruses navigate the host environment and will identify host and viral factors that contribute to the disparate outcomes of infection that are sometimes observed. This proposal will also introduce new tools and methodologies for investigating the spatial organization and dynamics of influenza virus infection.


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: 2025 ( Subtotal = $377,088 )
2025	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	000	3	2/13/2025	NON-COMPETING CONTINUATION	$377,088
														Subtotal = $377,088

Issue Date FY: 2024 ( Subtotal = $388,750 )
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Allergy and Infectious Diseases Research	000	2	12/20/2023	NON-COMPETING CONTINUATION	$349,875
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Allergy and Infectious Diseases Research	001	2	5/23/2024	NON-COMPETING CONTINUATION	$38,875
														Subtotal = $388,750

Issue Date FY: 2023 ( Subtotal = $389,584 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	000	1	2/16/2023	NEW	$389,584
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	001	1	4/6/2023	NEW	$0
														Subtotal = $389,584

Grand Total All Awards = $1,155,422

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Genetic and biophysical mechanisms that control influenza virus cellular multiplicity of infection

Award Number: R01AI171445

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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