Drosophila melanogaster larvae are tolerant to oral infection with the bacterial pathogen Photorhabdus luminescens.

The fruit fly Drosophila melanogaster is an excellent model for dissecting the molecular and functional bases of bacterial pathogenicity and host antibacterial immune response. The Gram-negative bacterium Photorhabdus luminescens is an insect-specific pathogen that forms a mutualistic relationship with the entomopathogenic nematode Heterorhabditis bacteriophora . Here we find that oral infection of D. melanogaster larvae with P. luminescens moderately reduces their survival ability while the bacteria replicate efficiently in the infected insects. This information will contribute towards understanding host gut immunity against potent bacterial pathogens.

Drosophila melanogaster Imd signaling interacts with insulin signaling and alters feeding rate upon parasitic nematode infection.

Significant progress has been made in recent years on exploring immunometabolism, a field that integrates two processes essential for maintaining tissue and organismal homeostasis, immunity and metabolism. The nematode parasite Heterorhabditis gerrardi, its mutualistic bacteria Photorhabdus asymbiotica, and the fruit fly Drosophila melanogaster constitute a unique system to investigate the molecular basis of host immunometabolic response to nematode-bacterial complexes. In this study, we explored the contribution of the two major immune signaling pathways, Toll and Imd, to sugar metabolism in D. melanogaster larvae during infection with H. gerrardi nematodes. We infected Toll or Imd signaling loss-of-function mutant larvae with H. gerrardi nematodes and assessed larval survival ability, feeding rate, and sugar metabolism. We found no significant differences in the survival ability or levels of sugar metabolites in any of the mutant larvae when responding to H. gerrardi infection. However, we found that the Imd mutant larvae have higher feeding rate than controls during the early stages of infection. In addition, feeding rates are lower in Imd mutants relative to the control larvae as the infection progresses. We further showed that Dilp2 and Dilp3 gene expression increases in Imd mutants compared to controls early in the infection, but their expression levels decrease at later times. These findings indicate that Imd signaling activity regulates the feeding rate and Dilp2 and Dilp3 expression in D. melanogaster larvae infected with H. gerrardi. Results from this study facilitate our understanding of the link between host innate immunity and sugar metabolism in the context of infectious diseases caused by parasitic nematodes.

Activin and BMP Signaling Activity Affects Different Aspects of Host Anti-Nematode Immunity in Drosophila melanogaster.

The multifaceted functions ranging from cellular and developmental mechanisms to inflammation and immunity have rendered TGF-ß signaling pathways as critical regulators of conserved biological processes. Recent studies have indicated that this evolutionary conserved signaling pathway among metazoans contributes to the Drosophila melanogaster anti-nematode immune response. However, functional characterization of the interaction between TGF-ß signaling activity and the mechanisms activated by the D. melanogaster immune response against parasitic nematode infection remains unexplored. Also, it is essential to evaluate the precise effect of entomopathogenic nematode parasites on the host immune system by separating them from their mutualistic bacteria. Here, we investigated the participation of the TGF-ß signaling branches, activin and bone morphogenetic protein (BMP), to host immune function against axenic or symbiotic Heterorhabditis bacteriophora nematodes (parasites lacking or containing their mutualistic bacteria, respectively). Using D. melanogaster larvae carrying mutations in the genes coding for the TGF-ß extracellular ligands Daw and Dpp, we analyzed the changes in survival ability, cellular immune response, and phenoloxidase (PO) activity during nematode infection. We show that infection with axenic H. bacteriophora decreases the mortality rate of dpp mutants, but not daw mutants. Following axenic or symbiotic H. bacteriophora infection, both daw and dpp mutants contain only plasmatocytes. We further detect higher levels of Dual oxidase gene expression in dpp mutants upon infection with axenic nematodes and Diptericin and Cecropin gene expression in daw mutants upon infection with symbiotic nematodes compared to controls. Finally, following symbiotic H. bacteriophora infection, daw mutants have higher PO activity relative to controls. Together, our findings reveal that while D. melanogaster Dpp/BMP signaling activity modulates the DUOX/ROS response to axenic H. bacteriophora infection, Daw/activin signaling activity modulates the antimicrobial peptide and melanization responses to axenic H. bacteriophora infection. Results from this study expand our current understanding of the molecular and mechanistic interplay between nematode parasites and the host immune system, and the involvement of TGF-ß signaling branches in this process. Such findings will provide valuable insight on the evolution of the immune role of TGF-ß signaling, which could lead to the development of novel strategies for the effective management of human parasitic nematodes.

The Drosophila melanogaster Metabolic Response against Parasitic Nematode Infection Is Mediated by TGF-ß Signaling.

The nematode Heterorhabditis bacteriophora, its mutualistic bacterium Photorhabdus luminescens, and the fruit fly Drosophila melanogaster establish a unique system to study the basis of infection in relation to host metabolism. Our previous results indicate that the Transforming Growth Factor ß (TGF-ß) signaling pathway participates in the D. melanogaster metabolic response against nematode parasitism. However, our understanding of whether the presence of Photorhabdus bacteria in Heterorhabditis nematodes affects the metabolic state of D. melanogaster during infection is limited. Here, we investigated the involvement of TGF-ß signaling branches, Activin and Bone Morphogenetic Protein (BMP), in the D. melanogaster metabolic response against axenic (lacking bacteria) or symbiotic (containing bacteria) H. bacteriophora infection. We show that BMP signaling mediates lipid metabolism against axenic or symbiotic H. bacteriophora and alters the size of fat body lipid droplets against symbiotic nematode infection. Also, following symbiotic H. bacteriophora infection, Activin signaling modulates sugar metabolism. Our results indicate that Activin and BMP signaling interact with the D. melanogaster metabolic response to H. bacteriophora infection regardless of the presence or absence of Photorhabdus. These findings provide evidence for the role of TGF-ß signaling in host metabolism, which could lead to the development of novel treatments for parasitic diseases.