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Receptor recognition and cell entry of coronaviruses

Award Number: R01AI089728
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: 05/15/2010
PERIOD OF PERFORMANCE END DATE: 05/31/2021

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Receptor recognition and cell entry of coronaviruses - Receptor recognition and cell entry by viruses are two initial and essential steps in viral infection cycles. They are important determinants of viral host ranges, tissue tropisms and pathogenesis, and are primary targets for human intervention. Coronaviruses (CoVs) pose serious health threats to humans and other animals. SARS-CoV and MERS-CoV have infected thousands of people with significant fatality, whereas porcine epidemic diarrhea CoV is currently causing ~100% fatality in piglets. A virus-surface spike protein guides CoV entry into host cells by binding to its host receptor via its S1 subunit and fusing viral and host membranes via its S2 subunit. S1 from different CoVs recognizes a variety of host receptors through one or both of its domains (S1-NTD and S1-CTD), and the S1/S2 boundary is cleaved by host proteases for activation of membrane fusion by S2. Our previous research has determined a number of crystal structures of CoV S1 domains by themselves or in complex with their respective receptor, and also shown how proteolysis regulates the cell entry of some CoVs. Our research has contributed critically to the current knowledge about the molecular mechanisms for CoV receptor recognition, cell entry, and cross-species transmission. In this competitive renewal of R01, we will continue to investigate how CoVs exploit host receptors and host proteases for cell entry. This proposal has three specific aims. Aim 1 examines receptor binding by CoV S1-NTDs. Specifically, we will investigate whether S1-NTDs from different CoV genera have the same structural fold and evolutionary origin as host galectins (galactose-binding lectins). We will also examine how CoV S1-NTDs recognize sugar receptors. These studies will reveal the evolutionary origins of CoV S1-NTDs, enhance understanding of sugar recognition by CoVs, and may facilitate future design of sugar analogues and subunit vaccines to inhibit CoV infections. Aim 2 focuses on receptor binding by CoV S1-CTDs. Specifically, we will analyze the interactions between the S1-CTDs of bat SARS-like CoVs (SL-CoVs) and the protein receptor homologues from humans and other animals, and elucidate how bat SL-CoVs transmitted to humans and other animals to cause the SARS epidemic through evolutionary changes in their S1-CTDs. These studies will provide critical information for understanding emergence potential of bat SL-CoVs and for facilitating epidemic monitoring and control. Aim 3 investigates cell entry by CoVs. Specifically, we will investigate what host proteases activate CoV entry and how the proteases motifs in CoV spikes have evolved to modulate CoV entry. These studies will reveal how host proteases regulate CoV entry to meet their specific need for host range, tissue tropism and pathogenesis, and may facilitate future design of protease inhibitors to block CoV entry. Overall, this proposal investigates the molecular and structural mechanisms for receptor recognition, cell entry, cross-species transmission, and tissue tropism of CoVs, which will lead to novel principles in virology. This research is also important for evaluating the emerging disease potentials of CoVs and for preventing, controlling and treating CoV infections in humans and other animals.


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: 2022 ( Subtotal = -$61 )
2022	2020	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Allergy and Infectious Diseases Research	000	10	11/11/2021	NON-COMPETING CONTINUATION	-$61
														Subtotal = -$61

Issue Date FY: 2020 ( Subtotal = $455,796 )
2020	2020	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Allergy and Infectious Diseases Research	000	10	5/29/2020	NON-COMPETING CONTINUATION	$455,796
														Subtotal = $455,796

Issue Date FY: 2019 ( Subtotal = $455,796 )
2019	2019	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Allergy and Infectious Diseases Research	000	9	5/24/2019	NON-COMPETING CONTINUATION	$455,796
														Subtotal = $455,796

Issue Date FY: 2018 ( Subtotal = $455,615 )
2018	2018	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Allergy and Infectious Diseases Research	000	8	5/23/2018	NON-COMPETING CONTINUATION	$455,615
														Subtotal = $455,615

Issue Date FY: 2017 ( Subtotal = $453,437 )
2017	2017	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Allergy and Infectious Diseases Research	000	7	5/15/2017	NON-COMPETING CONTINUATION	$453,437
														Subtotal = $453,437

Issue Date FY: 2016 ( Subtotal = $464,440 )
2016	2016	UNIVERSITY OF MINNESOTA, OFFICE OF STUDENT FINANCE AID	106 PLEASANT SE, 210 FRASER HL	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Allergy and Infectious Diseases Research	000	6	6/7/2016	COMPETING CONTINUATION	$464,440
														Subtotal = $464,440

Issue Date FY: 2014 ( Subtotal = $373,725 )
2014	2014	UNIVERSITY OF MINNESOTA, OFFICE OF STUDENT FINANCE AID	106 PLEASANT SE, 210 FRASER HL	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Allergy and Infectious Diseases Research	000	5	4/2/2014	NON-COMPETING CONTINUATION	$373,725
														Subtotal = $373,725

Issue Date FY: 2013 ( Subtotal = $351,302 )
2013	2013	UNIVERSITY OF MINNESOTA, OFFICE OF STUDENT FINANCE AID	106 PLEASANT SE, 210 FRASER HL	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Allergy and Infectious Diseases Research	001	4	6/5/2013	NON-COMPETING CONTINUATION	$14,949
2013	2013	UNIVERSITY OF MINNESOTA, OFFICE OF STUDENT FINANCE AID	106 PLEASANT SE, 210 FRASER HL	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Allergy and Infectious Diseases Research	000	4	4/11/2013	NON-COMPETING CONTINUATION	$336,353
														Subtotal = $351,302

Issue Date FY: 2012 ( Subtotal = $373,725 )
2012	2012	UNIVERSITY OF MINNESOTA, OFFICE OF STUDENT FINANCE AID	106 PLEASANT SE, 210 FRASER HL	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Allergy and Infectious Diseases Research	000	3	4/10/2012	NON-COMPETING CONTINUATION	$373,725
														Subtotal = $373,725

Issue Date FY: 2011 ( Subtotal = $373,725 )
2011	2011	UNIVERSITY OF MINNESOTA, OFFICE OF STUDENT FINANCE AID	106 PLEASANT SE, 210 FRASER HL	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Allergy and Infectious Diseases Research	001	2	6/8/2011	NON-COMPETING CONTINUATION	$33,975
2011	2011	UNIVERSITY OF MINNESOTA, OFFICE OF STUDENT FINANCE AID	106 PLEASANT SE, 210 FRASER HL	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Allergy and Infectious Diseases Research	000	2	4/20/2011	NON-COMPETING CONTINUATION	$339,750
														Subtotal = $373,725

Issue Date FY: 2010 ( Subtotal = $377,500 )
2010	2010	UNIVERSITY OF MINNESOTA, OFFICE OF STUDENT FINANCE AID	106 PLEASANT SE, 210 FRASER HL	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Allergy and Infectious Diseases Research	000	1	5/14/2010	NEW	$377,500
														Subtotal = $377,500

Grand Total All Awards = $4,135,000

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Receptor recognition and cell entry of coronaviruses

Award Number: R01AI089728

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: 05/15/2010

PERIOD OF PERFORMANCE END DATE: 05/31/2021

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