Regulators of the Toll and Imd pathways in the Drosophila innate immune response

doi:10.1016/j.it.2005.02.006

Trends in Immunology

Volume 26, Issue 4, April 2005, Pages 193-198

https://doi.org/10.1016/j.it.2005.02.006 Get rights and content

The innate immune response is the first line of defense against microbial infections in both insects and mammals. Systematic analysis of the innate immune response in the model organism Drosophila melanogaster has provided important insights into the mechanisms of pathogen recognition and host response. Recognition of pathogen-associated molecules, such as peptidoglycans, stimulates the Toll and immune deficiency (Imd) pathways to induce antimicrobial responses. The Toll and Imd pathways are homologous to the mammalian Toll-like receptor (TLR) and tumor necrosis factor receptor (TNFR) signaling pathways, respectively, and are essential for Drosophila to survive infection. In this Review, we will discuss the recent genetic, genomic and RNA interference analyses that have unveiled additional intricacy in the Toll and Imd pathways.

Section snippets

Signal-dependent regulation of the Drosophila antimicrobial response

On infection, insects mount a rapid antimicrobial response that consists of many components, such as antimicrobial peptides, complement-like proteins and blood cells 1, 2, 3, 4, 5, 6. Insects do not have counterparts of mammalian B and T lymphocytes, and therefore the insect antimicrobial response does not exhibit a high degree of antigen-targeting specificity. Nonetheless, insects can recognize different classes of microorganisms and respond differentially 7, 8, 9, 10. Moreover, the components

Pattern recognition in the Toll pathway

Toll is a transmembrane receptor first identified as an essential component in dorsal–ventral embryonic development in Drosophila [15]. Although many of the Toll pathway components were characterized based on their embryonic phenotypes, recent genetic studies using immune deficiency phenotypes (i.e. reduced survival of animals after septic injury or reduced immunity gene expression) have provided further insights into this pathway 16, 17, 18. Stimulation of the Toll pathway by Gram-positive

Novel insights into the mechanism of Toll signaling

Toll activation involves receptor multimerization. Using various chimeric and mutant constructs, it has been demonstrated that multimerization of Toll increases signaling activity 25, 26. Moreover, in vitro experiments have shown that a dimer of truncated Spätzle can link with two molecules of the Toll ectodomain, suggesting that an in vivo function of Spätzle is to induce the dimerization of Toll [24]. The contention of Toll and TLR multimerization fits well with published results 27, 28.

Pattern recognition in the Imd pathway

Imd is an adaptor protein homologous to the TNFR-interacting protein receptor interacting protein (RIP) [51]. The Imd pathway governs the expression of many antimicrobial peptide genes in response to Gram-negative bacterial infection 1, 2, 3, 4. The pattern-recognition receptor for the Imd pathway appears to be PGRP-LC, which contains a putative transmembrane domain 32, 33 (Figure 4). The loss-of-function mutants of another PGRP, the PGRP-LE, also cause reduced expression of antimicrobial

The Imd pathway has multiple branches

Many signaling components downstream of Imd have been identified by forward and reverse genetics 1, 2, 3, 4 (Figure 4). So far, TAK1 (transforming growth factor-β-activated kinase 1) is the most upstream kinase of the cascade. TAK1 activates the Drosophila IKK complex that contains at least the IKKβ and IKKγ homologues, which are encoded by the ird5 and kenny genes, respectively 18, 39, 40, 41, 42. The Drosophila IKK complex directs the site-specific proteolytic cleavage and activation of

Summary

The most significant findings in Drosophila innate immunity in the last few years are the identification of many upstream recognition molecules for various microorganisms and microbial compounds. The PGRP family of pattern-recognition receptors greatly expands our knowledge of the insect innate immune response and provides an interesting comparison to the Toll and TLR family. The Drosophila Toll and Imd pathways have been relatively well characterized, however, further understanding of these

Acknowledgements

The work in our laboratory is support by an NIH grant (GM53269).

References (55)

D. Hultmark
Drosophila immunity: paths and patterns
Curr. Opin. Immunol.
(2003)
M. Meister
Blood cells of Drosophila: cell lineages and role in host defence
Curr. Opin. Immunol.
(2004)
E. Kopp et al.
Recognition of microbial infection by Toll-like receptors
Curr. Opin. Immunol.
(2003)
P. Tzou
Tissue-specific inducible expression of antimicrobial peptide genes in Drosophila surface epithelia
Immunity
(2000)
S. Pili-Floury
In vivo RNA interference analysis reveals an unexpected role for GNBP1 in the defense against Gram-positive bacterial infection in Drosophila adults
J. Biol. Chem.
(2004)
A. Dunne
Structural complementarity of Toll/interleukin-1 receptor domains in Toll-like receptors and the adaptors Mal and MyD88
J. Biol. Chem.
(2003)
H.K. Lee
Cytoplasmic domain-mediated dimerizations of Toll-like receptor 4 observed by β-lactamase enzyme fragment complementation
J. Biol. Chem.
(2004)
T. Kaneko
Monomeric and polymeric gram-negative peptidoglycan but not purified LPS stimulate the Drosophila IMD pathway
Immunity
(2004)
T. Werner
Functional diversity of the Drosophila PGRP-LC gene cluster in the response to lipopolysaccharide and peptidoglycan
J. Biol. Chem.
(2003)
E. De Gregorio
An immune-responsive Serpin regulates the melanization cascade in Drosophila
Dev. Cell
(2002)

N. Silverman

Immune activation of NF-κB and JNK requires Drosophila TAK1

J. Biol. Chem.

(2003)

G. Bonizzi et al.

The two NF-κB activation pathways and their role in innate and adaptive immunity

Trends Immunol.

(2004)

M. Elrod-Erickson

Interactions between the cellular and humoral immune responses in Drosophila

Curr. Biol.

(2000)

F. Leulier

Inducible expression of double-stranded RNA reveals a role for dFADD in the regulation of the antibacterial response in Drosophila adults

Curr. Biol.

(2002)

S. Hu et al.

dFADD, a novel death domain-containing adapter protein for the Drosophila caspase DREDD

J. Biol. Chem.

(2000)

P. Chen

Dredd, a novel effector of the apoptosis activators reaper, grim, and hid in Drosophila

Dev. Biol.

(1998)

P. Georgel

Drosophila immune deficiency (IMD) is a death domain protein that activates antibacterial defense and can promote apoptosis

Dev. Cell

(2001)

R.S. Khush

A ubiquitin-proteasome pathway represses the Drosophila immune deficiency signaling cascade

Curr. Biol.

(2002)

M. Boutros

Sequential activation of signaling pathways during innate immune responses in Drosophila

Dev. Cell

(2002)

J.A. Hoffmann

The immune response of Drosophila

Nature

(2003)

B. Lemaitre

The road to Toll

Nat. Rev. Immunol.

(2004)

C.A. Brennan et al.

Drosophila: the genetics of innate immune recognition and response

Annu. Rev. Immunol.

(2004)

D.L. Bodian

Cytokines in Drosophila hematopoiesis and cellular immunity

Prog. Mol. Subcell. Biol.

(2004)

B. Lemaitre

Drosophila host defense: differential induction of antimicrobial peptide genes after infection by various classes of microorganisms

Proc. Natl. Acad. Sci. U. S. A.

(1997)

F. Leulier

The Drosophila immune system detects bacteria through specific peptidoglycan recognition

Nat. Immunol.

(2003)

V. Bischoff

Function of the Drosophila pattern-recognition receptor PGRP-SD in the detection of Gram-positive bacteria

Nat. Immunol.

(2004)

A. Takehana

Peptidoglycan recognition protein (PGRP)-LE and PGRP-LC act synergistically in Drosophila immunity

EMBO J.

(2004)

Cited by (220)

The Toll/IMD pathways mediate host protection against dipteran parasitoids
2024, Journal of Insect Physiology
Parasitoids have utilized a variety of strategies to counteract host defense. They are in different taxonomic status and exhibit phenotypic and genetic diversity, and thus are thought to evolve distinct anti-defense mechanisms. In this study, we investigated the performance of two closely related parasitoids, Exorista japonica and Exorista sorbillans (Diptera: Tachinidae) that are biological control agents in agriculture and major insect pests in sericulture, on the host Bombyx mori. We show that the host is more susceptible to E. sorbillans infection while relatively resistant to E. japonica infection. Moreover, the expression levels of host antimicrobial peptides (AMPs) genes are repressed at early infection and induced at late infection of E. japonica, while AMPs are over-expressed at early infection and return to normal levels at late infection of E. sorbillans. In parallel, Toll and IMD pathway genes are generally induced at late infection of E. japonica, whereas these genes are up-regulated at early infection and down-regulated at late infection of E. sorbillans. Activating of host Toll/IMD pathways and AMPs expression by lipopolysaccharide (LPS) represses the larval growth of E. sorbillans. Conversely, inhibiting host Toll/IMD pathways by RNA interference significantly promotes E. japonica development. Therefore, the Toll/IMD pathways are required in the host for defense against infection of dipteran parasitoids. Overall, our study provides the new insight into the diversified host-parasitoid interactions, and offers a theoretical basis for further studies of the adaptive mechanism of dipteran parasitoids.
Relish-facilitated lncRNA-CR11538 suppresses Drosophila Imd immune response and maintains immune homeostasis via decoying Relish away from antimicrobial peptide promoters
2024, Developmental and Comparative Immunology
Innate immunity plays a crucial role in host defense against pathogen invasion and its strength and duration requires precise control. Long non-coding RNAs (lncRNAs) have become important regulators of innate immunity, yet their roles in Drosophila immune responses remain largely unknown. In this study, we identified that the overexpression of lncRNA-CR11538 inhibits the expression of antimicrobial peptides (AMPs) Dpt and AttA in Drosophila upon Escherichia coli (E. coli) infection, and influences the survival rate of flies after E. cloacae infection. Mechanically, lncRNA-CR11538 decoys Relish away from AMPs promoter region. We further revealed that Relish can promote the transcription of lncRNA-CR11538. After analyzing the dynamic expression profile of lncRNA-CR11538 during Imd immune response, we put forward a hypothesis that in the late stage of Imd immune response, lncRNA-CR11538 can be activated by Relish and further decoy Relish away from the AMPs promoter to suppress excessive immune signal and maintain immune homeostasis. This mechanism we proposed provides insights into the complex regulatory networks controlling immune responses in Drosophila and suggests potential targets for therapeutic intervention in diseases involving dysregulated immune responses.
Histopathological observations and comparative transcriptome analysis of Ophiocordyceps sinensis infection of Hepialus xiaojinensis in the early stage
2024, Developmental and Comparative Immunology
Hepialus xiaojinensis is a Lepidopteran insect and one of the hosts for the artificial cultivation of Cordyceps. Ophiocordyceps sinensis can infect and coexist with H. xiaojinensis larvae for a long time. Little studies focused on the interaction process through its early infection stage. In this research, we particularly study the interaction of infected and uninfected larvae in the 3rd (OS-3, CK-3) and 4th (OS-4, CK-4) instars. O. sinensis was distributed within the larvae and accompanied by pathological changes in some tissue structures. In response to O. sinensis infection, OS-3 enhanced the antioxidant defense ability, while OS-4 decreased. The transcriptome analysis showed that OS-3 resisted the invasion of O. sinensis by the immune and nervous systems. Correspondingly, OS-4 reduced immune response and utilized more energy for growth and development. This study provides a comprehensive resource for analyzing the mechanism of H. xiaojinensis and O. sinensis interaction.
PTBP1 suppresses porcine epidemic diarrhea virus replication via inducing protein degradation and IFN production
2023, Journal of Biological Chemistry
Porcine epidemic diarrhea virus (PEDV) causes severe morbidity and mortality among newborn piglets. It significantly threatens the porcine industry in China and around the globe. To accelerate the developmental pace of drugs or vaccines against PEDV, a deeper understanding of the interaction between viral proteins and host factors is crucial. The RNA-binding protein, polypyrimidine tract–binding protein 1 (PTBP1), is crucial for controlling RNA metabolism and biological processes. The present work focused on exploring the effect of PTBP1 on PEDV replication. PTBP1 was upregulated during PEDV infection. The PEDV nucleocapsid (N) protein was degraded through the autophagic and proteasomal degradation pathways. Moreover, PTBP1 recruits MARCH8 (an E3 ubiquitin ligase) and NDP52 (a cargo receptor) for N protein catalysis and degradation through selective autophagy. Furthermore, PTBP1 induces the host innate antiviral response via upregulating the expression of MyD88, which then regulates TNF receptor–associated factor 3/ TNF receptor–associated factor 6 expression and induces the phosphorylation of TBK1 and IFN regulatory factor 3. These processes activate the type Ⅰ IFN signaling pathway to antagonize PEDV replication. Collectively, this work illustrates a new mechanism related to PTBP1-induced viral restriction, where PTBP1 degrades the viral N protein and induces type Ⅰ IFN production to suppress PEDV replication.
Molecular evolution of the pathogen recognition peptidoglycan proteins regulates the immune response against infectious diseases in Drosophila melanogaster
2023, Journal of King Saud University - Science
The study aimed to understand the molecular evolution of the pathogen recognition peptidoglycan (PGN) proteins and their role in regulating the immune response against infectious diseases in Drosophila melanogaster. D. melanogasterWe obtained the PGRP proteins from 11 different species of Drosophila and analyzed the different evolutionary trends that might be associated with them. We were able to identify the evidence of strong positive selection taking place for these proteins. We investigated the diversity and function of the PGN proteins in D. melanogaster and related species through a combination of bioinformatics approaches. They found that the PGN proteins have undergone rapid and diverse evolution, with some undergoing positive selection and others experiencing gene duplication and loss. The study also revealed that different PGN proteins play distinct roles in regulating the immune response to bacterial infections, with some responding specifically to certain types of bacteria. The research provides valuable insights into the evolution and function of the PGN proteins in the immune response of D. melanogaster. It highlights their potential relevance to pathogen recognition and immune defence in other organisms.
Microbiota aggravates the pathogenesis of Drosophila acutely exposed to vehicle exhaust
2022, Heliyon
Vehicle exhaust (VE) is the primary cause of urban air pollution, which adversely affects the respiratory system, exacerbates lung diseases, and results in high mortality rates. However, the underlying mechanism of the pathogenesis is largely unclear. Here, we developed a Drosophila model to systematically investigate the effects of VE on their health and physiology. We found that VE significantly impaired life span and locomotion in Drosophila. Interestingly, there was an increase in bacterial load in the guts upon VE exposure, suggesting VE is able to induce dysbiosis in the guts. Microbiota depletion can ameliorate the impairment of life span and locomotion. VE causes permeability of intestinal epithelial cells and increases proliferation of intestinal cells, suggesting VE disrupts intestinal homeostasis. We elucidate the underlying mechanism by which VE triggers Imd and DUOX gene expression. Taken together, this Drosophila model provides insight into the pathogenesis of Drosophila exposure to VE, enabling us to better understand the specific role of microbiota.

View all citing articles on Scopus

View full text

Trends in Immunology

Regulators of the Toll and Imd pathways in the Drosophila innate immune response

Section snippets

Signal-dependent regulation of the Drosophila antimicrobial response

Pattern recognition in the Toll pathway

Novel insights into the mechanism of Toll signaling

Pattern recognition in the Imd pathway

The Imd pathway has multiple branches

Summary

Acknowledgements

Curr. Opin. Immunol.

Curr. Opin. Immunol.

Curr. Opin. Immunol.

Immunity

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Immunity

J. Biol. Chem.

Dev. Cell

J. Biol. Chem.

Trends Immunol.

Curr. Biol.

Curr. Biol.

J. Biol. Chem.

Dev. Biol.

Dev. Cell

Curr. Biol.

Dev. Cell

The immune response of Drosophila

Nature

The road to Toll

Nat. Rev. Immunol.

Drosophila: the genetics of innate immune recognition and response

Annu. Rev. Immunol.

Cytokines in Drosophila hematopoiesis and cellular immunity

Prog. Mol. Subcell. Biol.

Drosophila host defense: differential induction of antimicrobial peptide genes after infection by various classes of microorganisms

Proc. Natl. Acad. Sci. U. S. A.

The Drosophila immune system detects bacteria through specific peptidoglycan recognition

Nat. Immunol.

Function of the Drosophila pattern-recognition receptor PGRP-SD in the detection of Gram-positive bacteria

Nat. Immunol.

Peptidoglycan recognition protein (PGRP)-LE and PGRP-LC act synergistically in Drosophila immunity

EMBO J.