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Role of Complement in Nipah Virus Pathogenesis

Award Number: R21AI132375
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: 05/25/2017
PERIOD OF PERFORMANCE END DATE: 04/30/2020

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Role of Complement in Nipah Virus Pathogenesis - The complement system is a critical part of innate immune responses that most animal viruses encounter during natural infections. Complement is an important factor in neutralization of many RNA viruses, but the role it plays in pathogenesis and dissemination during paramyxovirus infections is largely unknown. Here, we seek to fill gaps in our understanding of interactions of complement with the highly pathogenic paramyxovirus Nipah virus (NiV). This project emerged from our recent published finding that NiV virions recruit complement Factor I as a novel mechanism to prevent neutralization, and that Factor I binds the NiV F protein on cell surfaces. These important findings raise the questions of: 1) what role NiV recruitment of this host cell inhibitor plays in blocking complement pathways at the cell surface and in preventing complement-mediated cell lysis, and 2) the role of complement in NiV infections of animals. Here, we will define mechanisms and functional consequences for NiV recruitment of Factor I to the cell surface (Aim 1) and the role of complement in either enhancing or restricting NiV tissue tropism and pathogenesis (Aim 2). Our preliminary data have shown that Complement Factor I binds to the surface of cells expressing the NiV F protein but not the G protein. In Aim 1, we will use biochemical approaches and cell culture experiments to determine the requirements for F-mediated recruitment of Factor I. Functional assays will determine the effect of F protein-Factor I interactions on which complement pathways are activated at the cell surface and the extent of antibody-dependent and -independent cell lysis. We hypothesize that complement pathways could act to inhibit NiV dissemination. Alternatively, complement could promote NiV dissemination and disease, especially given the importance of complement factors in lymphocyte recruitment and integrity of the blood brain barrier. In Aim 2, we will use a recently developed ferret model under BSL4 conditions to compare the course of NiV infection in the presence and absence of intact complement pathways. Time-course experiments will define the tissue-specific viral load (e.g., lung vs brain), changes in tissue pathological lesions and overall clinical outcomes. There is intense interest in defining mechanisms that modulate the interplay between host innate immune systems, such as complement, and emerging paramyxoviruses with the potential for bioterrorism. By establishing the above key feasibility issues with this R21 Exploratory/Developmental grant mechanism, we will be in an excellent position for more advanced mechanistic studies using animal models.


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: 2021 ( Subtotal = -$3 )
2021	2018	UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES, THE	4000 CENTRAL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Allergy and Infectious Diseases Research	000	2	11/9/2020	NON-COMPETING CONTINUATION	-$3
														Subtotal = -$3

Issue Date FY: 2018 ( Subtotal = $187,560 )
2018	2018	UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES, THE	4000 CNTRL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Allergy and Infectious Diseases Research	000	2	3/28/2018	NON-COMPETING CONTINUATION	$187,560
														Subtotal = $187,560

Issue Date FY: 2017 ( Subtotal = $235,560 )
2017	2017	UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES, THE	4000 CNTRL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Allergy and Infectious Diseases Research	000	1	5/23/2017	NEW	$235,560
														Subtotal = $235,560

Grand Total All Awards = $423,117

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Role of Complement in Nipah Virus Pathogenesis

Award Number: R21AI132375

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: 05/25/2017

PERIOD OF PERFORMANCE END DATE: 04/30/2020

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