Thursday, November 21, 2024 11/21/2024

Regulation of Rotavirus Replication, Virulence, and Host Range Restriction by the Innate Immune System

Award Number: R01AI125249
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY/ABSTRACT Rotaviruses (RVs) are highly infectious viruses of great importance because they are the most common cause of severe gastroenteritis in young children. We will address three fundamental topics in rotavirology (RV) that will expand our understanding of the molecular mechanisms regulating RV innate immune evasion. 1. Determine the structural basis and in vivo activity of NSP1-mediated β-TrCP degradation. Despite the RV NSP1 protein's well-documented ability to induce IRF3 and/or β-TrCP degradation, the mechanisms regulating this degradation are unknown. Human RV NSP1s specifically target β-TrCP. We have recently identified an unexpected role of the host Cullin-E3 ligase complex in NSP1's degradative functions. In this aim we will dissect how NSP1 is able to hijack the host Cullin-E3 ligase complex, induce β- TrCP degradation, block NF-κB activation and thereby promote homologous RV replication. 2. Identify the molecular mechanisms underlying MAVS degradation by VP3 in a strain- and host- specific fashion both in vitro and in vivo. We previously showed that ssRNA byproducts from RV infection are potent activators of cytosolic sensors RIG-I and MDA5, both of which converge on mitochondrial antiviral signaling protein (MAVS) to relay innate signaling and induce IFN expression. Unexpected preliminary findings suggest that MAVS is targeted for proteasomal degradation by the RV VP3 protein in a host range restricted (HRR) manner. Here we will explore the complex interplay between VP3 and MAVS from different RV species at a mechanistic level and evaluate the importance of VP3-mediated MAVS degradation in promoting RV replication in vitro and in vivo. 3. Identify the mechanism of RV NSP1-mediated inhibition of STAT1 activation and the intestinal cell origin of the IFN responses to RV infection. Despite the ability to efficiently suppress the induction of type I IFN in intestinal epithelial cells (IECs), homologous RV infection still induces substantial levels of type I and III IFNs in the gut. This IFN production suggests that RVs must be able to subvert IFN-mediated antiviral amplification as well as blocking IFN induction. RV NSP1 efficiently inhibits IFN-mediated STAT1 phosphorylation. New findings indicate RV blocks STAT1 activation by depleting multiple IFN receptors, likely by NSP1-directed degradation. RVs can also block IFN-directed STAT1 activation in uninfected cells in vitro. Whether this effect also occurs in vivo is unknown. We propose to identify the hematopoietic cell and IEC origins of type I and III IFNs elicited by RV infection. We will also examine the mechanistic determinants of RV-mediated IFN receptor degradation and inhibition of STAT1 activation and determine if differences in these functions contribute to RV HRR.


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 = -$71,758 )
2024	2021	PALO ALTO VETERANS INSTITUTE FOR RESEARCH	3801 MIRANDA AVE	PALO ALTO	CA	94304	SANTA CLARA	USA	Allergy and Infectious Diseases Research	000	5	12/20/2023	NON-COMPETING CONTINUATION	-$71,758
														Subtotal = -$71,758

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	PALO ALTO VETERANS INSTITUTE FOR RESEARCH	3801 MIRANDA AVE BLDG 101 A2-210	PALO ALTO	CA	94304	SANTA CLARA	USA	Allergy and Infectious Diseases Research	000	5	12/30/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $471,572 )
2021	2021	PALO ALTO VETERANS INSTITUTE FOR RESEARCH	3801 MIRANDA AVE BLDG 101 A2-210	PALO ALTO	CA	94304	SANTA CLARA	USA	Allergy and Infectious Diseases Research	000	5	1/13/2021	NON-COMPETING CONTINUATION	$471,572
														Subtotal = $471,572

Issue Date FY: 2020 ( Subtotal = $471,572 )
2020	2020	PALO ALTO VETERANS INSTITUTE FOR RESEARCH	3801 MIRANDA AVE BLDG 101 A2-210	PALO ALTO	CA	94304	SANTA CLARA	USA	Allergy and Infectious Diseases Research	000	4	1/29/2020	NON-COMPETING CONTINUATION	$471,572
														Subtotal = $471,572

Issue Date FY: 2019 ( Subtotal = $471,572 )
2019	2019	PALO ALTO VETERANS INSTITUTE FOR RESEARCH	3801 MIRANDA AVE BLDG 101 A2-210	PALO ALTO	CA	94304	SANTA CLARA	USA	Allergy and Infectious Diseases Research	000	3	1/16/2019	NON-COMPETING CONTINUATION	$471,572
														Subtotal = $471,572

Issue Date FY: 2018 ( Subtotal = $471,572 )
2018	2018	PALO ALTO VETERANS INSTITUTE FOR RESEARCH	3801 MIRANDA AVE BLDG 101 A2-210	PALO ALTO	CA	94304	SANTA CLARA	USA	Allergy and Infectious Diseases Research	000	2	1/31/2018	NON-COMPETING CONTINUATION	$471,572
														Subtotal = $471,572

Issue Date FY: 2017 ( Subtotal = $588,837 )
2017	2017	PALO ALTO VETERANS INSTITUTE FOR RESEARCH	3801 MIRANDA AVE BLDG 101 A2-210	PALO ALTO	CA	94304	SANTA CLARA	USA	Allergy and Infectious Diseases Research	000	1	2/8/2017	NEW	$220,561
2017	2017	PALO ALTO VETERANS INSTITUTE FOR RESEARCH	3801 MIRANDA AVE BLDG 101 A2-210	PALO ALTO	CA	94304	SANTA CLARA	USA	Allergy and Infectious Diseases Research	001	1	6/1/2017	NEW	$368,276
														Subtotal = $588,837

Grand Total All Awards = $2,403,367

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Regulation of Rotavirus Replication, Virulence, and Host Range Restriction by the Innate Immune System

Award Number: R01AI125249

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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