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Molecular and cellular dissection of the pathogenesis of herpes simplex encephalitis with iPSC-derived CNS and PNS cells

Award Number: R01NS072381
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary Herpes simplex virus 1 (HSV-1) encephalitis (HSE) is the most common sporadic viral encephalitis in Western countries. Forebrain HSE (which develops via olfactory neurons) in otherwise healthy children can result from inborn errors of the TLR3 pathway (mutations in TLR3, UNC93B1, TRIF, TRAF3, TBK1, and IRF3), whereas brainstem HSE (via trigeminal (TG) neurons) can result from inborn errors of RNA lariat metabolism (DBR1). Children with a broader defect of impaired production of (NEMO) or response to all IFNs (STAT1) are prone to HSE and other infections. We analyzed the cellular basis of HSE by deriving peripheral and central nervous system (PNS and CNS) cells from induced pluripotent stem cells (iPSC) (NIH R01NS072381). TLR3-deficient forebrain cortical neurons and oligodendrocyte precursors have impaired anti-HSV-1 cell-intrinsic immunity, unlike astrocytes and neural stem cells; microglial cells were not tested. Moreover, iPSC-derived TG neurons do not rely on TLR3 to control HSV-1; olfactory neurons were not tested. Finally, TLR3 controls both basal IFN levels and early steps of anti-HSV-1 immunity in cortical neurons. Childhood HSE results thus from inborn errors of non-hematopoietic, CNS-specific, cell-intrinsic immunity, affecting cortical neurons and oligodendrocytes in particular. We have since identified new forebrain HSE-causing genes that are connected to the TLR3-IFN circuit (MEX3B, IFNAR1), the TLR3-necroptosis pathway (RIPK3), and of unknown function (SNORA31, TMEFF1). In this renewal application, we hypothesize that genetic etiologies of forebrain HSE impair intrinsic immunity in cortical but not olfactory neurons, and in oligodendrocytes and probably microglial cells, and DBR1 deficiency impairs intrinsic immunity in brainstem and/or TG neurons and probably microglial cells. First, we will assess the responses of iPSC-derived olfactory and cortical neurons, and other CNS cells, from controls and patients mutated in new forebrain HSE-causing genes, to TLR3, IFN-a/ß or IFN-¿, and HSV-1 stimulation. Second, we will study RNA lariat accumulation, immunity to HSV-1 infection, and responses to IFN-a/ß or IFN- ¿, in control and DBR1-deficient iPSC-differentiated TG and brainstem neurons. Third, the role of microglial cells in forebrain vs brainstem HSE will be assessed by studying the responses to TLR3 agonists, IFN-a/ß, IFN-¿ and HSV-1, in isolation and in neuronal co-culture. Patient and isogenic iPSC lines in which the mutation is corrected or introduced by gene editing will be used. Cell-intrinsic immunity to HSV-1 and its molecular basis will be analyzed. Exciting preliminary data have been obtained, including (1) novel genetic etiologies of HSE, (2) novel mechanisms by which TLR3 controls HSV-1 in cortical neurons, and (3) novel protocols to differentiate brainstem neurons and microglial cells. The expand of this human iPSC-based study of HSE will enable us to dissect in greater breadth and depth its molecular and cellular basis in children with inborn errors of CNS-intrinsic immunity to HSV-1.


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 = $598,225 )
2024	2024	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	14	4/8/2024	NON-COMPETING CONTINUATION	$43,172
2024	2024	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	14	3/13/2024	NON-COMPETING CONTINUATION	$555,053
														Subtotal = $598,225

Issue Date FY: 2023 ( Subtotal = $624,524 )
2023	2023	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	13	3/7/2023	NON-COMPETING CONTINUATION	$624,524
														Subtotal = $624,524

Issue Date FY: 2022 ( Subtotal = $632,121 )
2022	2022	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	12	3/24/2022	NON-COMPETING CONTINUATION	$632,121
														Subtotal = $632,121

Issue Date FY: 2021 ( Subtotal = $654,756 )
2021	2021	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	11	3/16/2021	NON-COMPETING CONTINUATION	$654,756
2021	2021	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	11	3/18/2021	NON-COMPETING CONTINUATION	$0
2021	2020	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	10	5/22/2021	COMPETING CONTINUATION	$8,745
2021	2018	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	9	5/22/2021	NON-COMPETING CONTINUATION	-$8,745
														Subtotal = $654,756

Issue Date FY: 2020 ( Subtotal = $693,952 )
2020	2020	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	10	5/22/2020	COMPETING CONTINUATION	$693,952
2020	2018	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	5/15/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $693,952

Issue Date FY: 2018 ( Subtotal = $675,297 )
2018	2018	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	7/18/2018	NON-COMPETING CONTINUATION	$675,297
														Subtotal = $675,297

Issue Date FY: 2017 ( Subtotal = $680,371 )
2017	2017	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	7/19/2017	NON-COMPETING CONTINUATION	$680,371
														Subtotal = $680,371

Issue Date FY: 2016 ( Subtotal = $685,563 )
2016	2016	ROCKEFELLER UNIVERSITY	EAST 66TH STREET & YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	7/20/2016	NON-COMPETING CONTINUATION	$685,563
														Subtotal = $685,563

Issue Date FY: 2015 ( Subtotal = $688,969 )
2015	2015	ROCKEFELLER UNIVERSITY	EAST 66TH STREET & YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	7/14/2015	NON-COMPETING CONTINUATION	$688,969
														Subtotal = $688,969

Issue Date FY: 2014 ( Subtotal = $747,234 )
2014	2014	ROCKEFELLER UNIVERSITY	EAST 66TH STREET & YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	5	6/23/2014	COMPETING CONTINUATION	$4,790
2014	2014	ROCKEFELLER UNIVERSITY	EAST 66TH STREET & YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	6/3/2014	COMPETING CONTINUATION	$742,327
2014	2014	ROCKEFELLER UNIVERSITY	EAST 66TH STREET & YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	6/11/2014	COMPETING CONTINUATION	$117
														Subtotal = $747,234

Issue Date FY: 2013 ( Subtotal = $666,795 )
2013	2013	ROCKEFELLER UNIVERSITY	EAST 66TH STREET & YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	7/18/2013	NON-COMPETING CONTINUATION	$666,795
														Subtotal = $666,795

Issue Date FY: 2012 ( Subtotal = $698,366 )
2012	2012	ROCKEFELLER UNIVERSITY	EAST 66TH STREET & YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	7/18/2012	NON-COMPETING CONTINUATION	$698,366
														Subtotal = $698,366

Issue Date FY: 2011 ( Subtotal = $705,674 )
2011	2011	ROCKEFELLER UNIVERSITY	EAST 66TH STREET & YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	7/18/2011	NON-COMPETING CONTINUATION	$721,954
2011	2011	ROCKEFELLER UNIVERSITY	EAST 66TH STREET & YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	7/22/2011	NON-COMPETING CONTINUATION	-$16,280
														Subtotal = $705,674

Issue Date FY: 2010 ( Subtotal = $744,629 )
2010	2010	ROCKEFELLER UNIVERSITY	EAST 66TH STREET & YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/20/2010	NEW	$744,629
														Subtotal = $744,629

Grand Total All Awards = $9,496,476

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Molecular and cellular dissection of the pathogenesis of herpes simplex encephalitis with iPSC-derived CNS and PNS cells

Award Number: R01NS072381

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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