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Integration of mononuclear phagocytes into the human gastrointestinal GOFlowChip for investigation of luminal antigen sampling

Award Number: U01EB029242
ORGANIZATION: NATIONAL INSTITUTE Of BIOMEDICAL IMAGING & BIOENGINEERING
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Summary The emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly infectious human respiratory tract pathogen that has the capacity to infect many different organ systems, including the gastrointestinal (GI) tract. The overall goal of this project is to elucidate the role of the GI mucosa in SARS- CoV-2 infection and transmission. Specifically, we seek to identify mucosal immune mechanisms involved in COVID-19 pathogenesis and compare epithelial responses to SARS-CoV-2 in the gut of humans and bats. Investigating bat cells is important, because bats are considered the original hosts for SARS-CoV-2, but do not develop overt disease upon infection. Our recently developed GOFlowChip platform, which integrates 3- dimensional GI organoids and immune cells on a millifluidic chip with luminal and basolateral flow capacity, is ideally suited to probe the mechanisms involved in SARS-CoV-2 infection of the gut mucosa. Here, we propose to utilize the GOFlowChip to elucidate mechanisms of viral infection, replication and spread involved in SARS-CoV-2 infection of the GI tract. Specifically, we seek to (1) Define how SARS-CoV-2 infection of the GI epithelium contributes to viral spread. (2) Determine to what extent GI mucosal immune mechanisms regulate SARS-CoV-2 infection and spreading in the GI tract. (3) Compare GI epithelial responses to SARS- CoV-2 between bats and humans. For Specific Aim 1, we will optimize the GOFlowChip for use under BSL-3 laboratory conditions, followed by SARS-CoV-2 infection experiments that will elucidate susceptibility and viral replication dynamics in different gut compartments. Specific Aim 2 will leverage our organoid-mononuclear phagocyte (MNP) co-culture system to elucidate whether MNP-dependent transport mechanisms impact viral invasion of the GI mucosa, and we will screen SARS-CoV-2 reactive patient sera for their ability to modulate gut infection. For Specific Aim 3, we will establish organoid lines from bat GI tissues in order to compare epithelial responses to SARS-CoV-2 in bats and humans using RNA sequencing in order to understand differences in viral pathogenicity between humans and bats. The proposed work is directly integrated with our existing project, because we will use out GOFlowChip to investigate how SARS-CoV-2 interacts with epithelial cells and immune system components to cross the GI barrier. Our research is technologically innovative, because we are using gut organoid-immune cell co-cultures in a fully contained tissue chip design to study a BSL-3 level pathogen. Our project is conceptually innovative, because it is the first to compare gut organoids from Jamaican fruit bats to human organoids for their ability to sustain SARS-CoV-2 infection and to mount cellular antiviral responses. The proposed research is significant because it will yield crucial information on the role of the GI mucosa in COVID-19 pathogenesis that may inform future strategies to identify viral carriers, prevent viral transmission, and design novel antiviral treatments and vaccines.


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: 2023 ( Subtotal = $611,538 )
2023	2023	MONTANA STATE UNIVERSITY	216 MONTANA HALL	BOZEMAN	MT	59717	GALLATIN	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	5	8/2/2023	NON-COMPETING CONTINUATION	$611,538
														Subtotal = $611,538

Issue Date FY: 2022 ( Subtotal = $611,538 )
2022	2022	MONTANA STATE UNIVERSITY	216 MONTANA HALL	BOZEMAN	MT	59717	GALLATIN	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	001	4	9/1/2022	NON-COMPETING CONTINUATION	$611,538
2022	2021	MONTANA STATE UNIVERSITY	216 MONTANA HALL	BOZEMAN	MT	59717	GALLATIN	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	3	1/28/2022	NON-COMPETING CONTINUATION	$0
2022	2021	MONTANA STATE UNIVERSITY	216 MONTANA HALL	BOZEMAN	MT	59717	GALLATIN	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	002	3	9/16/2022	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $611,538

Issue Date FY: 2021 ( Subtotal = $1,140,707 )
2021	2021	MONTANA STATE UNIVERSITY	216 MONTANA HALL	BOZEMAN	MT	59717	GALLATIN	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	003	2	6/2/2021	SUPPLEMENT FOR EXPANSION	$0
2021	2021	MONTANA STATE UNIVERSITY	216 MONTANA HALL	BOZEMAN	MT	59717	GALLATIN	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	004	3	8/3/2021	NON-COMPETING CONTINUATION	$599,308
2021	2021	MONTANA STATE UNIVERSITY, INC	211 MONTANA HALL	BOZEMAN	MT	59717	GALLATIN	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	002	2	3/23/2021	SUPPLEMENT FOR EXPANSION	$79,051
2021	2021	MONTANA STATE UNIVERSITY	216 MONTANA HALL	BOZEMAN	MT	59717	GALLATIN	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	005	3	8/16/2021	SUPPLEMENT FOR EXPANSION	$462,348
2021	2020	MONTANA STATE UNIVERSITY, INC	211 MONTANA HALL	BOZEMAN	MT	59717	GALLATIN	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	2	2/17/2021	SUPPLEMENT FOR EXPANSION	$0
2021	2020	MONTANA STATE UNIVERSITY, INC	211 MONTANA HALL	BOZEMAN	MT	59717	GALLATIN	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	001	2	3/23/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,140,707

Issue Date FY: 2020 ( Subtotal = $1,105,333 )
2020	2020	MONTANA STATE UNIVERSITY, INC	211 MONTANA HALL	BOZEMAN	MT	59717	GALLATIN	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	2	9/14/2020	NON-COMPETING CONTINUATION	$611,545
2020	2020	MONTANA STATE UNIVERSITY, INC	211 MONTANA HALL	BOZEMAN	MT	59717	GALLATIN	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	001	2	9/22/2020	SUPPLEMENT FOR EXPANSION	$493,788
														Subtotal = $1,105,333

Issue Date FY: 2019 ( Subtotal = $565,366 )
2019	2019	MONTANA STATE UNIVERSITY, INC	307 MONTANA HALL	BOZEMAN	MT	59717	GALLATIN	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	1	9/17/2019	NEW	$565,366
														Subtotal = $565,366

Grand Total All Awards = $4,034,482

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Integration of mononuclear phagocytes into the human gastrointestinal GOFlowChip for investigation of luminal antigen sampling

Award Number: U01EB029242

ORGANIZATION: NATIONAL INSTITUTE Of BIOMEDICAL IMAGING & BIOENGINEERING

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

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