# Activation of Insect Immunity by Gram-negative Bacteria

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2020 · $518,372

## Abstract

Abstract
 Innate immunity is an ancient defense response that evolved with the earliest metazoan creatures, and is
the first line of defense 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 uses 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 the adaptive immune response. The Drosophila immune response is 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 innate immune responses
are highly conserved with mammals, and discoveries made in flies have been translated into important,
paradigm shifting, findings in mammals. Particularly relevant for this proposal are the conserved NF-κB
signaling pathways that drive the immediate response to infection, in both insects and mammals.
 In Drosophila, systemic microbial infections are recognized by two distinct NF-κB signaling pathways, the
Toll and immune deficiency (Imd) pathways. Both of these pathways are triggered by microbial cell walls and
drive the production of antimicrobial peptides and other immuno-protective molecules. In particular, the Imd
pathway is triggered by DAP-type peptidoglycan from the cell wall of certain bacteria. The long-term
objective of this proposal is to understand in molecular detail the mechanisms used by the Imd pathway to
trigger effective immune responses. The specific aims of this proposal address the molecular mechanisms
involved in peptidoglycan recognition and Imd signal transduction. Aim1 probes the function and regulation
of amyloid fibrils formed by both the peptidoglycan receptors and key adapter proteins in this pathway. Aim 2
is focused on the ubiquitin dynamics that temporally regulate the Imd pathway, involving both activating K63-
chains and response-limiting K48-polyubiquitination. Aim 3 involves the characterization of a new family of
transporters involved in delivering peptidoglycan fragments, e.g. muramyl-dipeptide and tracheal cytotoxin, to
cytosolic innate immune receptors, in flies and mammals.

## Key facts

- **NIH application ID:** 9836784
- **Project number:** 5R01AI060025-17
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Neal Silverman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $518,372
- **Award type:** 5
- **Project period:** 2004-02-15 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9836784

## Citation

> US National Institutes of Health, RePORTER application 9836784, Activation of Insect Immunity by Gram-negative Bacteria (5R01AI060025-17). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9836784. Licensed CC0.

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