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Dissecting catalytic and regulatory functions of nonsegmented negative strandRNA viral polymerases

Award Number: R01AI146172
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Group Awards By Issue Date FY or Funding FY:

View Award Abstract

Non-segmented negative strand (NNS) RNA viruses, such as rabies virus (RABV), human respiratory syncytial virus (HRSV), human parainfluenza virus type 3 (HPIV3), and Ebola virus (EBOV), pose continuing threats to human health, but there are currently no established prophylactic and/or therapeutic countermeasures against most NNS RNA viral diseases. NNS RNA viruses possess a multifunctional RNA-dependent RNA polymerase (RdRp) large (L) protein, which catalyzes all enzymatic reactions required for viral RNA biogenesis (e.g., RNA synthesis, 5'-capping, cap methylation at the guanine-N7- and ribose-2'-O-positions, 3'-polyadenylation). All these enzymatic activities of the L proteins are unique and potentially druggable. Our goals are to elucidate the molecular mechanisms of RNA synthesis and processing with the L proteins and to develop anti-viral agents against them. To dissect the roles of the L proteins in RNA biosynthesis, we have developed a number of in vitro rhabdoviral RNA synthesis and processing systems for prototypic vesicular stomatitis virus (VSV) and RABV. Using these systems, we discovered that rhabdoviral L proteins catalyze unconventional mRNA capping with a novel GDP polyribonucleotidyltransferase (PRNTase, EC 2.7.7.88) domain. However, the mechanisms of pre- mRNA capping and methylation coupled to mRNA chain elongation remain largely unknown. Furthermore, virus- specific functions of L proteins have not been studied. We hypothesize that L proteins catalyze common enzymatic reactions via evolutionary conserved elements, but manifest virus-specific functions via diversified elements. This hypothesis will be rigorously tested by the following specific aims: to elucidate the mechanisms of (1) co-transcriptional mRNA maturation by rhabdoviral L proteins, (2) cap formation by pneumoviral and paramyxoviral L proteins, and (3) transcription and replication by filoviral L proteins. In Aim 1, we will determine the timing and order of pre-mRNA processing by the VSV L protein during mRNA chain elongation, leading to a new model of co-transcriptional mRNA maturation by L proteins of rhabdoviruses and, by extension, other NNS RNA viruses. In Aim 2, we will reveal common and diversified functions of putative PRNTase and methyltransferase domains of the HRSV and HPIV3 L proteins in mRNA cap formation. In Aim 3, we will provide a novel model for genome replication by the EBOV L protein that is significantly different from that by other NNS RNA viral L proteins. Collectively, the proposed studies will open up a new frontier in understanding how diversified NNS L proteins carry out each step of RNA synthesis and processing together with their cognate co- factor proteins. Our studies will provide foundations for the future development of antiviral agents targeting unique L domains of these significant NNS RNA viruses.


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: 2023 ( Subtotal = $347,625 )
2023	2023	UNIVERSITY OF TOLEDO, THE	3000 ARLINGTON AVE	TOLEDO	OH	43614	LUCAS	USA	Allergy and Infectious Diseases Research	000	5	5/26/2023	NON-COMPETING CONTINUATION	$347,625
														Subtotal = $347,625

Issue Date FY: 2022 ( Subtotal = $347,625 )
2022	2022	UNIVERSITY OF TOLEDO, THE	3000 ARLINGTON AVE	TOLEDO	OH	43614	LUCAS	USA	Allergy and Infectious Diseases Research	000	4	5/24/2022	NON-COMPETING CONTINUATION	$347,625
														Subtotal = $347,625

Issue Date FY: 2021 ( Subtotal = $347,625 )
2021	2021	UNIVERSITY OF TOLEDO, THE	3000 ARLINGTON AVE	TOLEDO	OH	43614	LUCAS	USA	Allergy and Infectious Diseases Research	002	3	5/3/2021	NON-COMPETING CONTINUATION	$347,625
2021	2020	UNIVERSITY OF TOLEDO, THE	3000 ARLINGTON AVE	TOLEDO	OH	43614	LUCAS	USA	Allergy and Infectious Diseases Research	001	2	11/2/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$89,569
2021	2019	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	1	11/2/2020	NEW	-$89,569
														Subtotal = $347,625

Issue Date FY: 2020 ( Subtotal = $347,437 )
2020	2020	UNIVERSITY OF TOLEDO, THE	3000 ARLINGTON AVE	TOLEDO	OH	43614	LUCAS	USA	Allergy and Infectious Diseases Research	002	2	6/1/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2020	2020	UNIVERSITY OF TOLEDO, THE	3000 ARLINGTON AVE	TOLEDO	OH	43614	LUCAS	USA	Allergy and Infectious Diseases Research	001	2	5/28/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$347,437
2020	2019	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	1	5/28/2020	NEW	$0
														Subtotal = $347,437

Issue Date FY: 2019 ( Subtotal = $360,000 )
2019	2019	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	1	5/31/2019	NEW	$360,000
														Subtotal = $360,000

Grand Total All Awards = $1,750,312

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Dissecting catalytic and regulatory functions of nonsegmented negative strandRNA viral polymerases

Award Number: R01AI146172

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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