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Fungal spore sensing by MDA5 is necessary for antifungal immunity against Aspergillus fumigatus

Award Number: R01AI139133
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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This R01 renewal application seeks to extend our initial observation that the cytosolic RNA-sensing pattern- recognition receptor MDA5 plays a critical role in regulating the alveolar macrophage-mediated host resistance against the human fungal pathogen Aspergillus fumigatus. Mechanistic understanding of how alveolar macrophages keep fungal infections at bay in immune competent individuals remains ill-defined. Currently, there is a critical gap in understanding how the early host-pathogen interactions between fungi and alveolar macrophages work to drive fungal clearance and host resistance. Our data from the last funding period demonstrate a novel role of live fungal conidia in triggering the cytosolic RNA-sensing MDA5 receptor specifically in alveolar macrophages to initiate the host protective type I and type III interferon response. Thus, our central hypothesis is the lung specific programing of alveolar macrophages enables them to sense multiple vitality features of Aspergillus fumigatus isolates to serve as a central hub of inflammation and host resistance against this menacing fungal pathogen. In SA1 we identify features of alveolar macrophages that enable the effective type I and type III interferon response which are necessary for host resistance against A. fumigatus. This will be done using the adoptive transfer of a novel transgenic fetal-liver derived alveolar macrophage technology developed in our Co-I’s laboratory to our MavsCd11c conditional knock-out mouse line, which has been shown have a critical defect in host resistance against Aspergillus fumigatus. In SA2 we will mechanistically follow-up on our observation that there are fungal dsRNA-dependent and fungal dsRNA- independent mechanisms for triggering MDA5/MAVS activation. This will be done using novel isogenic pairs of Aspergillus fumigatus that are infected or not with a dsRNA mycovirus, as well as Aspergillus fumigatus mutants defective in mycotoxin production to identify the fungal effectors triggering MDA5/MAVS-dependent inflammatory responses. Overall, this research fills a critical knowledge gap regarding the molecular mechanisms of the host- pathogen interaction occurring in the lungs to drive the protective antifungal MDA5-dependent type I and type III interferon response induced by Aspergillus fumigatus in alveolar macrophages in both mice and humans.


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: 2025 ( Subtotal = $482,638 )
2025	2025	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Allergy and Infectious Diseases Research	000	6	10/30/2024	NON-COMPETING CONTINUATION	$482,638
														Subtotal = $482,638

Issue Date FY: 2024 ( Subtotal = $511,122 )
2024	2024	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Allergy and Infectious Diseases Research	002	5	9/3/2024	COMPETING CONTINUATION	$31,663
2024	2024	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Allergy and Infectious Diseases Research	003	5	9/11/2024	COMPETING CONTINUATION	$17,855
2024	2024	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Allergy and Infectious Diseases Research	001	5	11/24/2023	COMPETING CONTINUATION	$461,604
2024	2022	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Allergy and Infectious Diseases Research	000	4	11/23/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $511,122

Issue Date FY: 2022 ( Subtotal = $528,337 )
2022	2022	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Allergy and Infectious Diseases Research	000	4	7/26/2022	NON-COMPETING CONTINUATION	$528,337
														Subtotal = $528,337

Issue Date FY: 2021 ( Subtotal = $528,337 )
2021	2021	TRUSTEES OF DARTMOUTH COLLEGE	6001 PARKHURST HALL STE 207	HANOVER	NH	03755	GRAFTON	USA	Allergy and Infectious Diseases Research	000	3	7/8/2021	NON-COMPETING CONTINUATION	$528,337
														Subtotal = $528,337

Issue Date FY: 2020 ( Subtotal = $528,337 )
2020	2020	TRUSTEES OF DARTMOUTH COLLEGE	1 HINMAN DARTMOUTH COLLEGE	HANOVER	NH	03755	GRAFTON	USA	Allergy and Infectious Diseases Research	000	2	7/22/2020	NON-COMPETING CONTINUATION	$528,337
														Subtotal = $528,337

Issue Date FY: 2019 ( Subtotal = $536,537 )
2019	2019	TRUSTEES OF DARTMOUTH COLLEGE	1 HINMAN DARTMOUTH COLLEGE	HANOVER	NH	03755	GRAFTON	USA	Allergy and Infectious Diseases Research	000	1	7/31/2019	NEW	$536,537
														Subtotal = $536,537

Grand Total All Awards = $3,115,308

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Fungal spore sensing by MDA5 is necessary for antifungal immunity against Aspergillus fumigatus

Award Number: R01AI139133

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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