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

> **NIH NIH R01** · UNIVERSITY OF MASSACHUSETTS LOWELL · 2022 · $385,600

## Abstract

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 o...

## Key facts

- **NIH application ID:** 10399548
- **Project number:** 5R01AI146168-04
- **Recipient organization:** UNIVERSITY OF MASSACHUSETTS LOWELL
- **Principal Investigator:** Natalie C. Steinel
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $385,600
- **Award type:** 5
- **Project period:** 2019-06-10 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10399548

## Citation

> US National Institutes of Health, RePORTER application 10399548, The teleost melano-macrophage center response to immunization and helminth-mediated immunosuppression (5R01AI146168-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10399548. Licensed CC0.

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