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Neurotropic herpesvirus envelopment and microtubule-mediated transport

Award Number: R01AI125244
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: 03/15/2017
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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Neurotropic herpesvirus envelopment and microtubule-mediated transport - The Alphaherpesvirinae include pathogens of the nervous system such as herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) and the swine virus pseudorabies virus (PRV). Initial infection is commonly at mucosal epithelia such as the oral and anogenital mucosa for HSV, and nasal and oropharyngeal mucosa for PRV. Following replication in these tissues, progeny viral particles are released and infect the termini of adjacent sensory neurons. They then travel by microtubule-directed retrograde traffic along the axon to the neuronal cell body. The viral genome is ultimately delivered to the nucleus and persists as a circular dsDNA episome during ensuing latency in the trigeminal ganglia of humans (HSV-1) and swine (PRV). Periodic reactivation from latency is followed by viral gene expression, DNA replication and assembly of new capsids. These become packaged with the viral genome, emerge from the nucleus and bud into cytoplasmic organelles to generate enveloped, infectious viral particles in the organellar lumen. How and where these transport and envelopment events occur in alphaherpesvirus-infected neurons is poorly understood. Maturing alphaherpesvirus particles are transported from the neuronal cell body into and along the axon by microtubule-directed anterograde transport using kinesin motors. Infectious mature viral particles accumulate at the nerve terminal then are released to infect adjacent mucosal epithelia, leading to subsequent rounds of viral replication and spread. The identity of the kinesin motors utilized at each stage, the machinery used to recruit kinesins to trafficking virions and even the structure of the viral particle that traffics down the axon, whether non-enveloped capsids or capsids that have acquired envelopes in the neuronal cell body, are key questions that we address in this application. In Specific Aim 1 we investigate the function of the gE/gI-US9p membrane protein complex in recruitment of the kinesin motors KIF1A and KIF5 to HSV-1 and PRV. We also test an innovative hypothesis concerning the role of the large tegument protein UL36p in assembly of KIF5 onto trafficking virions. In Specific Aim 2 we use a novel “envelopment trap” to address the controversial question of where HSV-1 acquires its envelope, whether in the cell body or nerve terminal (the Married and Separate mechanisms, respectively) in a range of neuronal cell lines, human iPSC-derived Trigeminal Ganglia and explanted sensory neurons. We also test key questions concerning the mechanisms of kinesin recruitment during egress of HSV-1 and PRV via the Married and Separate pathways. This proposal is therefore focused on the three major events that underlie alphaherpesvirus transmission from the nervous system to mucosal surfaces following reactivation from latency: capsid envelopment, microtubule-directed trafficking, and anterograde axonal transport. The specific aims exploit the complementary in vitro and in vivo expertise of the two principal investigators, and our common interests and experience with the gE/gI-US9p complex and UL36p, to dissect the molecular mechanisms supporting recrudescent disease caused by these 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: 2026 ( Subtotal = $741,120 )
2026	2026	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	000	10	12/5/2025	NON-COMPETING CONTINUATION	$741,120
														Subtotal = $741,120

Issue Date FY: 2025 ( Subtotal = $725,905 )
2025	2025	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	000	9	11/6/2024	NON-COMPETING CONTINUATION	$725,905
														Subtotal = $725,905

Issue Date FY: 2024 ( Subtotal = $750,726 )
2024	2024	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	001	8	5/16/2024	NON-COMPETING CONTINUATION	$75,073
2024	2024	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	000	8	11/8/2023	NON-COMPETING CONTINUATION	$675,653
2024	2023	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	003	7	7/25/2024	COMPETING CONTINUATION	$105,263
2024	2021	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	002	6	7/25/2024	NON-COMPETING CONTINUATION	-$105,263
														Subtotal = $750,726

Issue Date FY: 2023 ( Subtotal = $670,730 )
2023	2023	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	001	7	12/1/2022	COMPETING CONTINUATION	$626,018
2023	2023	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	002	7	8/10/2023	COMPETING CONTINUATION	$44,712
2023	2021	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	000	6	12/1/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $670,730

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	000	6	8/29/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $715,297 )
2021	2021	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	000	6	2/24/2021	NON-COMPETING CONTINUATION	$715,297
														Subtotal = $715,297

Issue Date FY: 2020 ( Subtotal = $715,297 )
2020	2020	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	000	5	2/12/2020	NON-COMPETING CONTINUATION	$715,297
														Subtotal = $715,297

Issue Date FY: 2019 ( Subtotal = $715,297 )
2019	2019	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	002	4	3/4/2019	NON-COMPETING CONTINUATION	$715,297
2019	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	003	2	5/16/2019	NON-COMPETING CONTINUATION	-$98,760
2019	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	001	3	2/8/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$325,834
2019	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	004	3	5/16/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$98,760
2019	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	000	2	2/8/2019	NON-COMPETING CONTINUATION	-$325,834
														Subtotal = $715,297

Issue Date FY: 2018 ( Subtotal = $715,297 )
2018	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	000	2	2/19/2018	NON-COMPETING CONTINUATION	$715,297
														Subtotal = $715,297

Issue Date FY: 2017 ( Subtotal = $731,581 )
2017	2017	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	000	1	3/10/2017	NEW	$731,581
														Subtotal = $731,581

Grand Total All Awards = $6,481,250

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Neurotropic herpesvirus envelopment and microtubule-mediated transport

Award Number: R01AI125244

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: 03/15/2017

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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