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The role of stem-cell mediated midgut repair in the dynamics of mosquito infections

Award Number: R01AI148529
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: 06/05/2020
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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The role of stem-cell mediated midgut repair in the dynamics of mosquito infections - Project Summary Vector-borne diseases account for more than 17% of all infectious disease and cause more than 700,000 deaths annually 1. Mosquitoes alone cause 400,000 malaria deaths and transmit viruses to hundreds of millions 2. The vectorial capacity of mosquitoes depends on their ability to survive infection. The damaging effects of pathogenic invasion of the mosquito midgut are well-documented 15-22, but little is known about how mosquitoes tolerate this stress. Intestinal stem cell (ISC) mediated midgut epithelial repair is essential for Drosophila survival following oral ingestion of pathogens 33. The mosquito midgut epithelium contains ISC-like cells 27, 34, 37-39, but their functional significance for infection outcomes and mosquito survival is unknown. We propose to address this knowledge gap in vector biology by investigating the mosquito gut regenerative response to pathogenic invasion. The “black box” regarding the functional significance of ISCs in the mosquito midgut is part of a fundamental knowledge gap: physiological studies treat the mosquito midgut as a homogeneous whole, rather than a complex, regionally compartmentalized tissue comprised of multiple cell populations (e.g. enterocytes, enteroendocrine cells, and ISCs). The specific contributions of these cell types to gut-pathogen interactions have not been investigated. The proposed work will not only illuminate mosquito epithelial responses to infection at the cellular level but will lead to the creation of new and innovative tools for the broader vector biology community. The first two aims of this project are (A) to characterize gut epithelial cell dynamics in mosquitoes under conditions of homeostasis and oral infection and (B) to evaluate the role of midgut epithelial repair in mosquito infection outcomes. Aedes aegypti will be used as a model to determine what stimuli (including human pathogens) affect gut epithelial turnover rates, whether post-infection repair rebuilds the gut homeostatically or alters epithelial composition, what genetic pathways control midgut epithelial repair, and what role epithelial repair plays in vector survival and competence. Our third aim is (C) to determine the specific contributions of functionally differentiated cell populations to epithelial dynamics and infection response. We will use single-cell RNAseq/ATACseq to establish how many cell types compose the midgut epithelium, create new transgenic lines expressing fluorescent markers for important cell types (enteroendocrine cells and ISCs), and, using these lines, couple fluorescence-activated cell sorting with RNAseq to examine the transcriptional response of the three major cell types (enterocytes, enteroendocrine cells, and ISCs) to infection. Our study will fill a critical gap in our understanding of mosquito midgut regenerative responses to pathogenic invasion. Our long-term goal is to identify new targets for vector control strategies that disrupt gut regeneration and reduce survival of infected mosquitoes below the critical incubation threshold required for pathogen transmission. In addition to laying the groundwork for innovative control targets, we will create tools for the broader vector biology community, paving the way for novel discoveries in mosquito midgut physiology.


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 = $0 )
2026	2024	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Allergy and Infectious Diseases Research	000	5	3/10/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $514,052 )
2024	2024	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Allergy and Infectious Diseases Research	000	5	5/17/2024	NON-COMPETING CONTINUATION	$514,052
														Subtotal = $514,052

Issue Date FY: 2023 ( Subtotal = $514,052 )
2023	2023	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Allergy and Infectious Diseases Research	000	4	5/3/2023	NON-COMPETING CONTINUATION	$514,052
														Subtotal = $514,052

Issue Date FY: 2022 ( Subtotal = $510,396 )
2022	2022	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Allergy and Infectious Diseases Research	000	3	5/18/2022	NON-COMPETING CONTINUATION	$510,396
														Subtotal = $510,396

Issue Date FY: 2021 ( Subtotal = $507,145 )
2021	2021	REDACTED DUE TO PII		ITHACA	NY	14850	TOMPKINS	USA	Allergy and Infectious Diseases Research	000	2	5/11/2021	NON-COMPETING CONTINUATION	$507,145
														Subtotal = $507,145

Issue Date FY: 2020 ( Subtotal = $541,236 )
2020	2020	REDACTED DUE TO PII		ITHACA	NY	14850	TOMPKINS	USA	Allergy and Infectious Diseases Research	000	1	6/5/2020	NEW	$541,236
														Subtotal = $541,236

Grand Total All Awards = $2,586,881

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The role of stem-cell mediated midgut repair in the dynamics of mosquito infections

Award Number: R01AI148529

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: 06/05/2020

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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