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The role of cellular respiration in the survival of infectious spores of the fungal pathogen Cryptococcus

Award Number: F31AI197683
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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The role of cellular respiration in the survival of infectious spores of the fungal pathogen Cryptococcus - PROJECT SUMMARY Cryptococcus is an environmental human fungal pathogen that produces spores for dispersal. When spores are inhaled into mammalian lungs, germination and dissemination to other organs can lead to fatal meningoencephalitis due to overwhelming fungal burdens in the brain and surrounding tissues. Thus, for spores to cause disease, they must germinate into vegetatively growing yeast. The inhibition of germination is therefore a promising strategy for intervention in disease, but little is known about the germination process. The objective of this proposal is to identify spore-specific processes and pathways that could be targeted for inhibition to ultimately prevent cryptococcal disease in humans. In prior work, we used a high-throughput screen of small, drug-like molecules to discover novel germination inhibitors. Among these inhibitors, we identified a class of 12 molecules with a shared substructure that presumably target Complex II of the electron transport chain in a fungal-specific manner. However, our preliminary data paradoxically demonstrate that it is possible for Cryptococcus spores to germinate under extremely hypoxic conditions (<0.0001% oxygen) in which yeast growth is fully inhibited. Because Cryptococcus has been shown to be a non-fermentative, obligate aerobe, these findings reveal a fundamental knowledge gap in how spore respiration and metabolism operate during the essential process of germination. Additional preliminary data also demonstrate that this hypoxic germination is susceptible to chemical inhibitors of electron transport chain (ETC) Complexes I-III and alternative oxidase (Aox1) inhibitors. This finding suggests that the ETC is still active and contributes to hypoxic germination. Consistent with this finding is that AOX1 is significantly upregulated during hypoxic germination, which may maintain electron flow using either residual oxygen or an alternative electron acceptor. Based on these data, the central hypothesis of this proposal is that the active use of the ETC pathway, including Aox1, either using residual O2 or an alternative non-oxygen terminal electron acceptor contributes to the unique ability of Cryptococcus spores to germinate in the absence of detectable oxygen. To test this hypothesis, I will carry out experiments to determine how the electron transport chain functions in germinating spores. I will compare the transcriptomes of spores germinating in both hypoxic and normoxic conditions, quantify germination in these conditions in the presence of ETC complex inhibitors, quantify ETC-associated metabolites and cofactors throughout germination, and investigate the potential for a non-oxygen terminal electron acceptor. This proposed work, conducted at a university with fungal research leaders, will improve our understanding of pathogenic spore germination, revealing processes to be targeted by therapeutics.


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 = $44,819 )
2026	2026	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	000	1	8/14/2026	NEW	$44,819
2026	2026	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	001	1	8/14/2026	NEW	$0
														Subtotal = $44,819

Grand Total All Awards = $44,819

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The role of cellular respiration in the survival of infectious spores of the fungal pathogen Cryptococcus

Award Number: F31AI197683

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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