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The teleost melano-macrophage center response to immunization and helminth-mediated immunosuppression

Award Number: R01AI146168
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Abstract Non-mouse models can be fertile ground for the discovery of previously unappreciated immunologic paradigms and provide new perspectives of vertebrate immunity. The proposed work addresses a fundamental question of bony fish (teleost) immunity: are melano-macrophage centers (MMC) the sites where fish B cells proliferate and generate high affinity antibody, homologous to germinal centers (GC) in mammals? To answer this long- standing question, we will characterize the threespine stickleback (Gasterosteus aculeatus) MMC response. Clarifying MMC function will yield important insights into the basis of humoral adaptive immunity in fish, and the evolutionary origins of vertebrate adaptive immunity. The first Aim of this project will investigate MMC function in response to immunization. To determine if MMCs are the site of B cell proliferation, immunized fish will be pulse labeled with BrdU so that proliferating BrdU+ cells can be localized. Next, to clarify whether somatic hypermutation occurs in MMCs, we will quantify immunoglobulin gene mutations in MMC-adjacent and non- adjacent B cells. To resolve if MMC function is indeed GC-like, we will compare the MMC response to immunization with T-dependent (NP-CGG) and T-independent (NP-dextran) antigens. The results of this first Aim will determine the suitability of the MMC as a biomarker of teleost humoral adaptive immunity, and whether the MMC is an “evolutionarily primitive” GC. Preliminary data strongly support our hypothesis that MMCs are GC-like. Consequently, in our second Aim we will apply our knowledge of MMC function to investigate the immuno-modulatory effects of a helminth parasite, Schistocephalus solidus. By combining experimental infection and immunization we will determine whether this tapeworm suppresses teleost adaptive immunity. We find that some stickleback genotypes are refractory to this immunosuppression. Using a combination of Quantitative Trait Locus (QTL) mapping, population genomics, and RNAseq analysis of gene expression we will locate the host loci responsible for variable parasite-mediated immune-modulation. We will then use the CRISPR/Cas9 system to modify these genes in cultured MMCs and evaluate their role in MMC function in vitro. In the final Aim, we will identify the helminth-derived factors that dampen MMC activity. Through QTL mapping we will identify the tapeworm-specific loci responsible for MMC suppression. To complement this approach, we will assess whether helminth excretory/secretory products directly modulate MMC gene expression. Clarifying the mechanistic basis of helminth-mediated immunomodulation in fish may reveal new approaches to regulate vertebrate immune function. This work will also generate a new and broadly applicable assay of teleost immunity, which has the potential to be used in the study of diverse fish (and other poikilotherm) species. Beyond expanding our view of vertebrate immunobiology, this work has implications for the disciplines of disease ecology, host-pathogen co-evolution, and vaccine development.


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: 2023 ( Subtotal = $385,600 )
2023	2023	UNIVERSITY OF MASSACHUSETTS	600 SUFFOLK ST STE 212	LOWELL	MA	01854	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	5	5/30/2023	NON-COMPETING CONTINUATION	$385,600
														Subtotal = $385,600

Issue Date FY: 2022 ( Subtotal = $385,600 )
2022	2022	UNIVERSITY OF MASSACHUSETTS	600 SUFFOLK ST STE 415	LOWELL	MA	01854	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	4	5/26/2022	NON-COMPETING CONTINUATION	$385,600
														Subtotal = $385,600

Issue Date FY: 2021 ( Subtotal = $385,600 )
2021	2021	UNIVERSITY OF MASSACHUSETTS	600 SUFFOLK ST STE 415	LOWELL	MA	01854	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	3	4/29/2021	NON-COMPETING CONTINUATION	$385,600
														Subtotal = $385,600

Issue Date FY: 2020 ( Subtotal = $385,600 )
2020	2020	UNIVERSITY OF MASSACHUSETTS	600 SUFFOLK ST FL 2 S	LOWELL	MA	01854	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	2	5/5/2020	NON-COMPETING CONTINUATION	$385,600
														Subtotal = $385,600

Issue Date FY: 2019 ( Subtotal = $370,854 )
2019	2019	UNIVERSITY OF MASSACHUSETTS	600 SUFFOLK ST FL 2 S	LOWELL	MA	01854	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	1	6/10/2019	NEW	$370,854
														Subtotal = $370,854

Grand Total All Awards = $1,913,254

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The teleost melano-macrophage center response to immunization and helminth-mediated immunosuppression

Award Number: R01AI146168

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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