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Mechanism and Inhibition of Thogotovirus Entry

Award Number: R01AI173327
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 11/22/2022
PERIOD OF PERFORMANCE END DATE: 10/31/2027

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Mechanism and Inhibition of Thogotovirus Entry - The past decade has seen a significant increase in the incidence of emerging virus infections that transmit directly from animals to humans or are vectored by mosquitos and ticks. Changes in demographics and climatic factors likely contribute to this increase. In the United States, ticks are the dominant vector for transmitting arthropod borne diseases including the Thogotovirus, Bourbon virus (BRBV) which can cause fatal disease in humans. Like other enveloped viruses, entry of BRBV begins with attachment to host-cell receptor molecules with subsequent membrane fusion to deliver the contents of the virion into the host cell. Viral attachment and fusion proteins are targeted by antibodies that contribute to our natural immunity against viruses and are consequently a validated therapeutic target. The single envelope glycoprotein (GP) of BRBV is responsible for both attachment to cellular receptors and catalyzing fusion. BRBV GP is structurally related to the envelope glycoprotein G of vesicular stomatitis virus, gB of herpes simplex virus, and GP64 of baculovirus which collectively are termed class III fusogens. Our understanding of class III fusogens and their inhibition lags behind the class I and II viral fusogens, exemplified by influenza HA, and flavivirus E respectively. We have developed a set of unique tools and reagents that will allow us to characterize existing and newly developed monoclonal antibodies against BRBV GP both structurally and functionally. We will identify those that are potently neutralizing, identify their mechanism of inhibition, test the efficacy of neutralizing and non-neutralizing antibodies in a mouse model of disease, and identify the breadth of related thogotoviruses against which such antibodies function. Using chimeric VSV reporter viruses that depend on the GP of BRBV for infection, we will define the precise step in entry by which specific antibodies impede infection. We will also determine the entry pathway of BRBV into cells and define the host requirements for this process. In preliminary data, we carried out a CRISPR inactivation screen that identified glucosylceramide synthase (UGCG) as an important host factor for entry of BRBV into mammalian cells and demonstrate related thogotoviruses are also dependent upon UGCG. Using a combination of genetic approaches, coupled with pharmacological inhibition and imaging of single virions during entry, we will precisely delineate the requirement for UGCG in entry, and identify and characterize additional host factors coopted during this process. Genetic and structural studies will permit us to map the critical determinants on GP required to coopt host-factors during the entry pathway, which will synergize with our antibody studies to provide a detailed mechanistic picture of entry and its inhibition. Successful completion of the proposed studies will provide new insights into the mechanism and structural requirements for attachment, internalization and membrane fusion driven by a class III fusogen, uncover the mechanism by which the host glucosylceramide synthase functions in entry, and identify antibodies that target GP to block those critical functions.


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 = $700,837 )
2026	2026	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	000	4	12/8/2025	NON-COMPETING CONTINUATION	$700,837
														Subtotal = $700,837

Issue Date FY: 2025 ( Subtotal = $700,837 )
2025	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	000	3	1/14/2025	NON-COMPETING CONTINUATION	$700,837
														Subtotal = $700,837

Issue Date FY: 2024 ( Subtotal = $688,397 )
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Allergy and Infectious Diseases Research	000	2	11/1/2023	NON-COMPETING CONTINUATION	$619,558
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Allergy and Infectious Diseases Research	001	2	5/13/2024	NON-COMPETING CONTINUATION	$68,839
														Subtotal = $688,397

Issue Date FY: 2023 ( Subtotal = $695,774 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	000	1	11/21/2022	NEW	$695,774
														Subtotal = $695,774

Grand Total All Awards = $2,785,845

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Mechanism and Inhibition of Thogotovirus Entry

Award Number: R01AI173327

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 11/22/2022

PERIOD OF PERFORMANCE END DATE: 10/31/2027

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