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Using natural products to decipher essential host-parasite interactions in visceral leishmaniasis.

Award Number: R16AI189394
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: 09/10/2025
PERIOD OF PERFORMANCE END DATE: 08/31/2029

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Using natural products to decipher essential host-parasite interactions in visceral leishmaniasis. - 1 PROJECT SUMMARY: 2 Visceral leishmaniasis is a vector-borne neglected tropical disease (NTD) caused by Leishmania 3 donovani and Leishmania infantum. During infection, Leishmania parasites alter host responses in 4 innate immune cells, such as macrophages (MΦ’s), to ensure parasite survival and replication in the 5 parasitophorous vacuole (PV). Understanding the cellular pathways that are subverted during 6 Leishmania infections provides a unique opportunity to elucidate the host-parasite interactions 7 necessary for successful infection. The long-term goal of this project is to identify natural products 8 that modify host-parasite interactions required for parasite replication while engaging a diverse group 9 of undergraduate research students. The overall objective is to identify the mechanism of action of 10 sulforaphane (SFN) to determine its antileishmanial properties. We hypothesize that SFN modifies 11 host and parasite pathways to inhibit intracellular amastigote replication. Our hypothesis is based on 12 our recently published work that establishes SFN is an effective anti-parasitic compound that inhibits 13 both promastigote and amastigote replication. The rationale underlying this proposal is that a 14 systematic study of the mechanisms controlled by SFN will provide a better appreciation of how 15 Leishmania successfully replicate inside MΦ’s. The overall objective will be accomplished by pursing 16 the following two specific aims: 1) identify the extent to which SFN activates nuclear factor erythroid 17 2-related factor 2 (NRF2)-dependent and -independent pathways to inhibit Leishmania replication, 18 and 2) identify the extent to which SFN modifies host autophagic flux to decrease parasite levels. 19 Under the first aim, our working hypothesis is that SFN sustains host NRF2-dependent gene 20 expression during the infection to reduce amastigote replication. The NRF2 pathway will be activated 21 post-infection through SFN and specific NRF2 activators in both wild-type and NRF2 knockout MΦ’s. 22 Amastigote levels will be quantified through fluorescence microscopy. Host and parasite 23 transcriptomics will be quantified through bioinformatics analysis. The second aim, based on 24 preliminary data, indicates that SFN inhibits autophagy to increase the number of autophagosomes 25 thereby reducing the number of intracellular amastigotes. Autophagic flux will be quantified through 26 fluorescence microscopy and protein analysis of autophagy related proteins in WT and LAMP2 KO 27 MΦ’s. Amastigote levels will be quantified, and essential host proteins associated with amastigote 28 maturation in the PV will be determined by confocal microscopy. This proposal is significant because 29 the resulting mechanistic understanding of host-parasite interactions will clarify the role of NRF2 and 30 autophagy within the innate immune cells during parasitic infections within the PV.


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 = $130,000 )
2025	2025	FORT LEWIS COLLEGE	1000 RIM DR	DURANGO	CO	81301	LA PLATA	USA	Allergy and Infectious Diseases Research	000	1	9/8/2025	NEW	$130,000
														Subtotal = $130,000

Grand Total All Awards = $130,000

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Using natural products to decipher essential host-parasite interactions in visceral leishmaniasis.

Award Number: R16AI189394

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: 09/10/2025

PERIOD OF PERFORMANCE END DATE: 08/31/2029

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