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Interplay between the heat shock response and histidine kinase pathways in the thermally dimorphic fungal pathogen Histoplasma capsulatum

Award Number: R01AI137418
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 Histoplasma capsulatum is one of several systemic dimorphic fungal pathogens that switch their growth program from an infectious mold form in the soil to a pathogenic yeast form in mammalian hosts. H. capsulatum causes up to 25,000 life-threatening infections per year in the U.S. alone with up to 50% mortality rate, and is the most common cause of fungal respiratory infections in healthy hosts. Infection occurs when the soil is disrupted, facilitating dispersion of hyphal fragments or spores that are inhaled by humans. Spores and hyphal fragments are the primary infectious agents; however, once introduced into the host, the pathogen converts to a budding-yeast form, which survives and replicates within host macrophages. In the laboratory, the switch between the infectious and parasitic states is modeled by changing the growth temperature: cells grow in the filamentous form (hyphal) at room temperature, whereas growth at 37ºC is sufficient to trigger growth in the yeast form and expression of virulence factors. Despite its importance to human health, very little is known about how H. capsulatum senses and responds to human body temperature. Our prior research findings significantly contributed to the understanding of the molecular mechanism used by H. capsulatum to regulate cell morphology and virulence gene expression: we found that four transcriptional regulators, Ryp1,2,3,4, are the core components of a temperature-responsive intersecting regulatory network. In unpublished studies, we comprehensively identified Ryp-interacting proteins with potential regulatory roles. Among the diverse set of Ryp2-interacting proteins, we characterized a heat shock protein, Hsp90, and two proteins, Ssk1 and Skn7, with predicted response regulator domains. We found that Hsp90, Ssk1 and Skn7 regulate yeast phase growth in H. capsulatum. Hsp90 plays a key role in the heat shock response; and response regulators work with sensor histidine kinases and are often involved in sensing environmental signals. In this project, we propose to build upon our previous findings and fully characterize the involvement of the heat shock response and histidine kinase pathways in regulating Ryp proteins, cell morphology and virulence traits in H. capsulatum in response to host temperature. These studies will provide fundamental information on how cells sense temperature and turn on the appropriate virulence pathways in the host. Ultimately, the information obtained from this project can be used to develop therapeutics for H. capsulatum infections and help prevent other dimorphic fungal infections.


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: 2024 ( Subtotal = $0 )
2024	2023	J. CRAIG VENTER INSTITUTE, INC.	4120 CAPRICORN LN	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	5	7/17/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $487,500 )
2023	2023	J. CRAIG VENTER INSTITUTE, INC.	4120 CAPRICORN LN	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	5	7/27/2023	NON-COMPETING CONTINUATION	$487,500
														Subtotal = $487,500

Issue Date FY: 2022 ( Subtotal = $487,500 )
2022	2022	J. CRAIG VENTER INSTITUTE, INC.	4120 CAPRICORN LN	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	4	8/2/2022	NON-COMPETING CONTINUATION	$487,500
														Subtotal = $487,500

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2020	J. CRAIG VENTER INSTITUTE, INC.	4120 CAPRICORN LN	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	3	8/3/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $487,500 )
2020	2020	J. CRAIG VENTER INSTITUTE, INC.	4120 CAPRICORN LN	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	3	7/13/2020	NON-COMPETING CONTINUATION	$487,500
														Subtotal = $487,500

Issue Date FY: 2019 ( Subtotal = $487,500 )
2019	2019	J. CRAIG VENTER INSTITUTE, INC.	4120 CAPRICORN LN	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	2	7/10/2019	NON-COMPETING CONTINUATION	$487,500
														Subtotal = $487,500

Issue Date FY: 2018 ( Subtotal = $487,500 )
2018	2018	J. CRAIG VENTER INSTITUTE, INC.	4120 CAPRICORN LN	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	1	8/14/2018	NEW	$487,500
														Subtotal = $487,500

Grand Total All Awards = $2,437,500

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Interplay between the heat shock response and histidine kinase pathways in the thermally dimorphic fungal pathogen Histoplasma capsulatum

Award Number: R01AI137418

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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