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Mechanisms of Antibody-Dependent Enhancement of Dengue Disease

Award Number: R01AI137276
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: 09/24/2018
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Mechanisms of Antibody-Dependent Enhancement of Dengue Disease - ABSTRACT Instead of conferring protection, IgG antibodies against dengue virus (DENV) have been correlated with increased susceptibility to symptomatic dengue disease, as patients with pre-existing antibodies against DENV experience at a higher rate the symptomatic form of dengue disease, which often includes life-threatening complications. With over 2.5 billion people being at risk of DENV infection and with >100 million new infections occurring annually, DENV represents a tremendous burden to global human public health, necessitating the development of efficacious therapeutic or vaccination approaches to control DENV infection and disease. Using in vitro cellular assays, several studies have previously suggested that anti-DENV antibodies can mediate enhanced viral infection of Fcγ receptor (FcγR)-expressing myeloid cells; a phenomenon referred to as antibody dependent enhancement (ADE). However, ADE of viral replication alone cannot account for the complex pathophysiological features of symptomatic dengue disease, as well as for the wide spectrum of clinical disease severity observed among symptomatic patients. During the previous funding period, in collaborative studies with the Institute Pasteur in Cambodia, a DENV endemic area, we demonstrated that dengue disease susceptibility, as well as disease severity are associated with the induction of specific glycoforms of IgG antibodies (afucosylated) that exhibit increased affinity for the activating FcγRIII receptor. In parallel mechanistic studies, we developed a novel in vivo model of dengue disease that expresses the full array of human FcγRs and is permissive for DENV infection. Using this model, we demonstrated that a critical step in the in vivo pathogenesis of dengue disease is the engagement of FcγRIIIa on macrophages by afucosylated IgG antibodies, which are enriched in severe dengue cases. FcγRIIIa-afucosylated IgG antibody interactions result in aberrant macrophage activation, inflammatory sequelae, significant morbidity, and mortality. These findings implicate the FcγRIIIa- afucosylated Fc axis as the basis for dengue disease susceptibility and pathogenesis. Using a unique set of biospecimens from DENV-infected patients, as well as our recently developed mouse models of ADE of dengue disease, the proposed studies aim to (i) dissect the mechanisms that drive the induction of IgG Fc afucosylated glycoforms upon DENV infection and (ii) characterize the downstream effector responses that are initiated upon engagement of FcγRIIIa by afucosylated IgG antibodies and contribute to disease pathogenesis. We anticipate that our findings will significantly advance our understanding of the pathways that regulate IgG Fc glycan heterogeneity during DENV infection and drive dengue disease pathogenesis, having a broader impact on the study of immune responses against other viral pathogens that are characterized by aberrant IgG Fc fucosylation.


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 = $459,711 )
2026	2026	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	9	8/20/2026	NON-COMPETING CONTINUATION	$459,711
														Subtotal = $459,711

Issue Date FY: 2025 ( Subtotal = $459,711 )
2025	2025	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	001	8	8/20/2025	NON-COMPETING CONTINUATION	$459,711
2025	2022	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	5	12/20/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $459,711

Issue Date FY: 2024 ( Subtotal = $459,711 )
2024	2024	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	7	7/30/2024	NON-COMPETING CONTINUATION	$459,711
														Subtotal = $459,711

Issue Date FY: 2023 ( Subtotal = $477,086 )
2023	2023	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	6	6/16/2023	COMPETING CONTINUATION	$477,086
2023	2023	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	001	6	7/11/2023	COMPETING CONTINUATION	$0
														Subtotal = $477,086

Issue Date FY: 2022 ( Subtotal = $423,750 )
2022	2022	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	001	5	8/11/2022	NON-COMPETING CONTINUATION	$423,750
2022	2020	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	3	4/19/2022	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $423,750

Issue Date FY: 2021 ( Subtotal = $423,750 )
2021	2021	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	4	8/5/2021	NON-COMPETING CONTINUATION	$423,750
														Subtotal = $423,750

Issue Date FY: 2020 ( Subtotal = $988,749 )
2020	2020	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	2	5/18/2020	SUPPLEMENT FOR EXPANSION	$141,249
2020	2020	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	002	3	8/18/2020	SUPPLEMENT FOR EXPANSION	$423,750
2020	2020	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	001	3	8/17/2020	NON-COMPETING CONTINUATION	$423,750
														Subtotal = $988,749

Issue Date FY: 2019 ( Subtotal = $423,750 )
2019	2019	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	2	8/5/2019	NON-COMPETING CONTINUATION	$423,750
														Subtotal = $423,750

Issue Date FY: 2018 ( Subtotal = $423,750 )
2018	2018	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	1	9/21/2018	NEW	$423,750
														Subtotal = $423,750

Grand Total All Awards = $4,539,968

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Mechanisms of Antibody-Dependent Enhancement of Dengue Disease

Award Number: R01AI137276

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: 09/24/2018

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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