Monday, December 30, 2024 12/30/2024

Partial maturation in mosquito-borne flaviviruses: developing new approaches to characterize the role of lattice heterogeneity in fusion, infectivity, and antibody neutralization

Award Number: DP2AI164293
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Group Awards By:

View Award Abstract

PROJECT SUMMARY When a mosquito-borne flavivirus encounters a cell, it must adhere to a receptor on the cell surface, endocytose, and finally fuse with the endosomal membrane. To accomplish this, flaviviruses use an exterior lattice of 180 E proteins arrayed in a herringbone arrangement of 90 antiparallel dimers at neutral pH. Acidification in the late endosome induces a widespread conformational rearrangement, resulting in 60 outward-facing trimeric E spikes that can embed into the host membrane and pull the membranes together, fusing them and releasing the viral RNA into the host cytoplasm. Although flavivirus lattices are canonically described as 90 dimers lying flat (mature state) or 60 trimers facing outward (immature and fusion states), up to 50% of Dengue virions have incomplete maturation that results in a mosaic pattern of E dimers and trimers with different orientations. It is unknown whether mosaic lattices are less functional than their perfect counterparts due to steric hindrance of the conformational rearrangements, or alternatively might have certain advantages that explain why evolution has conserved their heterogeneous arrangement. This has strong consequences for the design of therapeutics, as the mature and immature patches have different epitope exposure and possibly different binding affinities for antibodies that are not well understood. We will explore this question through a combination of structural and functional studies performed on mosaic Dengue and West Nile viruses, using cryo-electron tomography and subtomogram averaging to determine the position and orientation of individual E proteins within the viral lattices, and designing new analyses to describe the heterogeneity of the viral population. We will evaluate how the mosaic surface affects fusion and antibody binding, and directly visualize the structure-function relationship by imaging viruses interacting with target membranes and cells. This approach will allow us to identify which areas of a mosaic lattice participate in adhesion or fusion, and whether functional virions favor more heterogeneous or homogeneous surfaces. Current structural biology is usually performed on samples that contain a large number of inactive virions; by imaging functional states directly, inactive virions are eliminated from analysis to facilitate identification of the structural states of the virus that should be prioritized in structure-based therapeutic and vaccine design. While this work will focus on the flavivirus lattice, functional lattices are ubiquitous in all the domains of life and play integral roles in human health and disease. The methods and analyses we develop to study flaviviruses will directly apply to other viruses, but will also potentially aid in understanding processes as diverse as bacterial chemotaxis, carbon fixation, and human cardiac muscle contraction.


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: 2024 ( Subtotal = $452,988 )
2024	2024	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE STE 1900	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Allergy and Infectious Diseases Research	000	3	12/12/2023	NON-COMPETING CONTINUATION	$407,689
2024	2024	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Allergy and Infectious Diseases Research	001	3	5/16/2024	NON-COMPETING CONTINUATION	$45,299
														Subtotal = $452,988

Issue Date FY: 2023 ( Subtotal = $458,994 )
2023	2023	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE STE 1900	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Allergy and Infectious Diseases Research	000	2	12/5/2022	NON-COMPETING CONTINUATION	$458,994
														Subtotal = $458,994

Issue Date FY: 2022 ( Subtotal = $425,620 )
2022	2022	PURDUE UNIVERSITY	155 S GRANT ST	WEST LAFAYETTE	IN	47907	TIPPECANOE	USA	Allergy and Infectious Diseases Research	000	1	1/20/2022	NEW	$425,620
														Subtotal = $425,620

Grand Total All Awards = $1,337,602

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Partial maturation in mosquito-borne flaviviruses: developing new approaches to characterize the role of lattice heterogeneity in fusion, infectivity, and antibody neutralization

Award Number: DP2AI164293

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer