# From Drosophila Immunity to Anti-Inflammatories

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2024 · $611,606

## Abstract

Abstract
 Innate immunity is an ancient defense response that evolved with the earliest metazoan creatures to
protect against microbial infection. These responses rely on the immediate recognition of microbes by
germline-encoded receptors, and drive the production of numerous chemical, biological, and cellular
responses to defend against infection. In the face of constant microbial assault, innate immunity is essential
for the survival of nearly all multicellular organisms. On the other hand, over-exuberant or inappropriate
innate immune responses are the underlying cause of morbidity and mortality associated with many
infectious, autoimmune, and autoinflammatory diseases. Thus, a thorough mechanistic understanding of
innate immunity has many potential applications in the development of the next generation of therapeutics.
This proposal exploits the fruit fly Drosophila melanogaster as a model for the study of innate immunity. Flies
offer many advantages for the study of innate immunity, including experimental tractability and a model
system without the complexity of adaptive immunity. The Drosophila immune response is also an excellent
model for vector insect species, and discoveries made in flies are being translated into new approaches to
control vector-borne diseases. Furthermore, many aspects of the Drosophila innate immune responses are
highly conserved with mammals, and this conservation has lead to paradigm shifting discoveries of Toll
receptors and NF-κB transcription factors. In the current cycle of this project, we have uncovered another
conserved aspect of innate immunity, implicating the SLC46 family of solute carriers in the delivery of
peptidoglycan fragments (muropeptides) to cytosolic innate immune receptors, in flies and mammals.
 In Drosophila, microbial infections are recognized by two distinct NF-κB signaling pathways, the Toll and
immune deficiency (Imd) pathways. The Imd pathway is triggered by DAP-type peptidoglycan from the cell
wall of certain bacteria, which binds and activates cell surface or the cytosolic receptors PGRP-LC or PGRP-
LE, respectively, and activates a NF-κB signal transduction system with significant similarity to the TNFR and
TLR/TRIF-dependent pathways in mammals. The long-term objective of this project is to understand in
molecular detail the mechanisms used by the Imd pathway to trigger effective immune responses, and to
translate key discoveries, made in this invertebrate model system, to mammals. In this proposal, we build on
past discoveries and move in important new directions, with two specific aims exploiting the Drosophila
model, and the third aim translating our recent discoveries to mammals. Aim1 investigates the expanded
SLC46 family of muropeptide transporters in flies, while Aim 2 is focused on the molecular and biochemical
mechanisms controlling signal transduction in the Drosophila Imd pathway. Aim 3 utilizes Slc46a2-/- mice to
elucidate the function of this transporter in the NOD1 path...

## Key facts

- **NIH application ID:** 10747437
- **Project number:** 5R01AI060025-20
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Neal Silverman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $611,606
- **Award type:** 5
- **Project period:** 2004-02-15 → 2027-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10747437

## Citation

> US National Institutes of Health, RePORTER application 10747437, From Drosophila Immunity to Anti-Inflammatories (5R01AI060025-20). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10747437. Licensed CC0.

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