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The role of TRIM2 and SIRPA in New World Arenavirus entry

Award Number: R01AI159290
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: 05/23/2022
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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The role of TRIM2 and SIRPA in New World Arenavirus entry - New world hemorrhagic fever arenaviruses (NWAs), such as Junín virus, are rodent-transmitted viruses that cause ~30% mortality when they zoonose into humans. The mechanism by the NWAs induce disease is still not certain, although it likely includes induction of high levels of cytokines by infected sentinel cells of the immune system, leading to endothelia and thrombocyte dysfunction and neurological disease. Survivors of Junín infection develop strong humoral immune responses, suggesting that controlling infection at early times post-infection is critical for virus clearance. Although an effective Junín virus vaccine has decreased disease incidence, sporadic cases of this as well as the other known and novel NWAs for which there are no vaccines or effective therapeutics still occur. It is well-established that the clade B pathogenic NWAs bind to transferrin receptor 1 and other receptors on the cell surface, but the steps leading to their entry from an acidic cellular compartment are not well-determined. We recently performed a siRNA screen with pseudotyped viruses bearing a pathogenic Junín glycoprotein with the goal of finding host genes involved in entry that could serve as therapeutic targets. We found that TRIM2, a member of the tripartite motif family that includes well-known members of the host's intrinsic defense against viral infections, limits NWA endocytosis into cells. By probing the TRIM2 interactome for other host proteins that block NWA infection, we discovered that SIRPA, a cell surface protein that inhibits macrophage phagocytosis of tumor and dead cells and erythrocytes, also decreases infection. Importantly, SIRPA, unlike TRIM2, inhibits infection by various human pathogenic viruses that require trafficking to an acidic compartment, including VSV, Zika virus, LCMV and Ebola and SARS-Cov-2 pseudoviruses. Our data suggest that TRIM2 and SIRPA act at the viral entry/internalization step. These finding suggests that there are common mechanisms that regulate virus endocytosis and phagocytosis. We propose here to further investigate the overlap between virus-mediated endocytosis and phagocytosis in vitro, ex vivo and in vivo in three aims that will 1) investigate the overlap in the NWA entry and phagocytosis pathways; 2) determine where TRIM2/SIRPA inhibition of infection occurs; and 3) use TRIM2, SIRPA and other relevant knockout mice to probe the roles of these proteins in cell-type specific and in vivo infection by replication-competent NWAs. In addition to providing mechanistic insight into the entry of NWAs into cells, these studies have the potential of increasing our understanding as to how host factors limit infection and could lead to new approaches to therapeutic intervention.


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 = $491,107 )
2026	2026	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Allergy and Infectious Diseases Research	000	5	4/27/2026	NON-COMPETING CONTINUATION	$491,107
														Subtotal = $491,107

Issue Date FY: 2025 ( Subtotal = $481,188 )
2025	2025	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Allergy and Infectious Diseases Research	000	4	5/1/2025	NON-COMPETING CONTINUATION	$481,188
														Subtotal = $481,188

Issue Date FY: 2024 ( Subtotal = $480,006 )
2024	2024	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Allergy and Infectious Diseases Research	000	3	4/15/2024	NON-COMPETING CONTINUATION	$480,006
														Subtotal = $480,006

Issue Date FY: 2023 ( Subtotal = $493,835 )
2023	2023	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Allergy and Infectious Diseases Research	000	2	5/10/2023	NON-COMPETING CONTINUATION	$493,835
														Subtotal = $493,835

Issue Date FY: 2022 ( Subtotal = $441,075 )
2022	2022	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Allergy and Infectious Diseases Research	001	1	6/10/2022	NEW	-$51,647
2022	2022	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Allergy and Infectious Diseases Research	000	1	5/20/2022	NEW	$492,722
														Subtotal = $441,075

Grand Total All Awards = $2,387,211

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The role of TRIM2 and SIRPA in New World Arenavirus entry

Award Number: R01AI159290

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: 05/23/2022

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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