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Evolution of Aspergillus fumigatus virulence

Award Number: R01AI130128
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: 09/25/2017
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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Evolution of Aspergillus fumigatus virulence - Project Summary. Fungal mediated disease progression is highlighted by populations of fungal cells that form a community referred to as a biofilm. For therapeutic success, contemporary antifungal therapies must be effective at the site of infection in the context of an established fungal biofilm. Critically, it is now clear that emergent properties arise from fungal biofilms that directly alter virulence, disease progression, and antifungal drug susceptibility. However, the mechanisms through which filamentous fungal biofilm emergent properties impact virulence, disease progression, and antifungal susceptibility remain a significant knowledge gap. The long-term goal of this project is focused on defining the molecular mechanisms of Aspergillus fumigatus biofilm mediated disease progression mechanisms to inform contemporary and novel therapeutic approaches. In the prior funding period, we made important progress that surprisingly revealed heterogeneity in A. fumigatus biofilm morphology across clinical isolates. Differences in biofilm morphology altered virulence and disease progression in vivo in murine models of aspergillosis. We discovered that long term growth in a low oxygen environment gives rise to a biofilm morphology we termed H-MORPH and that a novel fungal specific gene cluster that contains a protein with unknown function was sufficient for H-MOPRH formation. Significantly, we identified H-MORPH clinical isolates from both acute invasive aspergillosis patients and patients with chronic aspergillosis, suggesting H-MORPH can arise in human disease. We observed that H-MOPRH occurs in vivo in a murine model of invasive pulmonary aspergillosis and contributes to worse disease outcomes compared to the contrasting N-MORPH isolates. In aim 1, we will define the genetic pathway(s) that regulate A. fumigatus the development of this unique population level morphotype utilizing the newly discovered biofilm architecture factor (baf) gene family as a tool to dissect the underlying mechanisms. In aim 2, we will define the differences in fungal metabolism that underly N-MORPH and H-MORPH morphotypes and test the hypothesis that H- MORPH biofilms are carbon catabolite de-repressed which leads to increased fitness in vivo. In aim 3, we test the hypothesis that H-MORPH strain metabolism is immune modulatory through alterations in fungal pathogen associated molecular pattern exposure. Taken together, our proposed studies will fill significant knowledge gaps related to the discovery of distinct A. fumigatus morphotypes that directly impact virulence. Advancing our understanding of this knowledge gap is expected to lay the foundation for new diagnostic and therapeutic strategies to combat highly virulent and drug resistant strains of this important human fungal pathogen.


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 = $556,540 )
2026	2026	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Allergy and Infectious Diseases Research	000	9	6/19/2026	NON-COMPETING CONTINUATION	$556,540
														Subtotal = $556,540

Issue Date FY: 2025 ( Subtotal = $556,152 )
2025	2025	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Allergy and Infectious Diseases Research	000	8	7/14/2025	NON-COMPETING CONTINUATION	$556,152
														Subtotal = $556,152

Issue Date FY: 2024 ( Subtotal = $555,374 )
2024	2024	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Allergy and Infectious Diseases Research	000	7	6/24/2024	NON-COMPETING CONTINUATION	$555,374
2024	2023	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Allergy and Infectious Diseases Research	002	6	7/16/2024	COMPETING CONTINUATION	$41,485
2024	2021	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Allergy and Infectious Diseases Research	001	5	7/16/2024	NON-COMPETING CONTINUATION	-$41,485
														Subtotal = $555,374

Issue Date FY: 2023 ( Subtotal = $572,277 )
2023	2023	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Allergy and Infectious Diseases Research	001	6	7/11/2023	COMPETING CONTINUATION	$572,277
2023	2021	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Allergy and Infectious Diseases Research	000	5	6/30/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $572,277

Issue Date FY: 2021 ( Subtotal = $454,942 )
2021	2021	TRUSTEES OF DARTMOUTH COLLEGE	6001 PARKHURST HALL STE 207	HANOVER	NH	03755	GRAFTON	USA	Allergy and Infectious Diseases Research	000	5	8/11/2021	NON-COMPETING CONTINUATION	$454,942
														Subtotal = $454,942

Issue Date FY: 2020 ( Subtotal = $454,942 )
2020	2020	TRUSTEES OF DARTMOUTH COLLEGE	1 HINMAN DARTMOUTH COLLEGE	HANOVER	NH	03755	GRAFTON	USA	Allergy and Infectious Diseases Research	000	4	8/14/2020	NON-COMPETING CONTINUATION	$454,942
														Subtotal = $454,942

Issue Date FY: 2019 ( Subtotal = $454,942 )
2019	2019	TRUSTEES OF DARTMOUTH COLLEGE	1 HINMAN DARTMOUTH COLLEGE	HANOVER	NH	03755	GRAFTON	USA	Allergy and Infectious Diseases Research	000	3	8/13/2019	NON-COMPETING CONTINUATION	$454,942
														Subtotal = $454,942

Issue Date FY: 2018 ( Subtotal = $454,942 )
2018	2018	TRUSTEES OF DARTMOUTH COLLEGE	1 HINMAN DARTMOUTH COLLEGE	HANOVER	NH	03755	GRAFTON	USA	Allergy and Infectious Diseases Research	000	2	8/15/2018	NON-COMPETING CONTINUATION	$454,942
														Subtotal = $454,942

Issue Date FY: 2017 ( Subtotal = $473,975 )
2017	2017	TRUSTEES OF DARTMOUTH COLLEGE	1 HINMAN DARTMOUTH COLLEGE	HANOVER	NH	03755	GRAFTON	USA	Allergy and Infectious Diseases Research	000	1	9/25/2017	NEW	$473,975
														Subtotal = $473,975

Grand Total All Awards = $4,534,086

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Evolution of Aspergillus fumigatus virulence

Award Number: R01AI130128

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: 09/25/2017

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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