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Dissecting the mechanisms of intestinal epithelial injury by Ebola virus using iPSC-derived intestinal organoids

Award Number: R21AI167369
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary Filoviruses, including ebola- and marburgviruses, are prime examples of zoonotic viruses that cause severe disease in humans. The most pathogenic ebolavirus species is Ebola virus (Zaire ebolavirus; EBOV) with case fatality rates ranging from 40 to 90%. Many patients who succumb to the disease are admitted to Ebola treatment units when they are already severely ill. Importantly, there are no therapeutics available to mitigate late-stage Ebola Virus Disease (EVD). While many aspects of EBOV pathogenesis have been extensively studied in cell culture systems and animal models, the involvement of the intestine in EVD is not at all understood, despite diarrhea being among the most frequent symptoms (78% of patients in some case studies) and being one of the main causes for demise. Gastrointestinal manifestations, including vomiting, abdominal pain, and diarrhea, are also common symptoms of Marburg virus (MARV) disease. There are currently no infection models available that allow to study the consequences of filovirus infection of the gut. To fill this gap, we propose to establish human intestinal infection platforms to dissect the molecular mechanisms underlying filovirus-induced damage of the intestinal organs. We will explore two potential mechanisms that might play a role in the pathophysiological effects induced by filovirus infection: i) Filovirus infection of the human intestinal epithelium leads to loss of barrier integrity. ii) Filovirus infection of the human intestinal epithelium modulates the function of ion transporters. Identifying mechanisms that contribute to the induction of severe diarrhea in filovirus infection has the potential to inform urgently needed therapeutic approaches to mitigate the severe intestinal symptoms in late-stage filovirus disease. Human induced pluripotent stem cells (iPSCs) are capable of indefinite self-renewal and have the potential to differentiate into any tissue-specific cell lineage, including human intestinal organoids (HIOs). In preparation for this project, we have successfully achieved robust EBOV and MARV infections of iPSC-derived HIOs. The infected cells showed signs of cell damage, and transcriptomics analysis indicated the modulation of cell junction pathways and a set of ion transporters known to play a role in the induction of diarrhea. To begin to explore the intrinsic host response of intestinal cells to filovirus infection and the impact of infection-induced cellular damage on barrier integrity, we have designed the following specific aims: Specific Aim 1: To study the pathophysiological effects of EBOV and MARV infection on intestinal epithelial integrity. Specific Aim 2: To validate the role of individual genes by genetic ablation and test potential drug candidates as modulators of intestinal epithelial function.


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 = $212,500 )
2023	2023	BOSTON MEDICAL CENTER CORPORATION	1 BOSTON MEDICAL CTR PL STE 1	BOSTON	MA	02118	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	2	6/15/2023	NON-COMPETING CONTINUATION	$212,500
														Subtotal = $212,500

Issue Date FY: 2022 ( Subtotal = $273,750 )
2022	2022	BOSTON MEDICAL CENTER CORPORATION	1 BOSTON MEDICAL CTR PL STE 1	BOSTON	MA	02118	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	1	7/5/2022	NEW	$273,750
														Subtotal = $273,750

Grand Total All Awards = $486,250

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Dissecting the mechanisms of intestinal epithelial injury by Ebola virus using iPSC-derived intestinal organoids

Award Number: R21AI167369

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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