Bacteria-Derived Peptidoglycan Triggers a Noncanonical Nuclear Factor-κB-Dependent Response in Drosophila Gustatory Neurons.

Probing the external world is essential for eukaryotes to distinguish beneficial from pathogenic micro-organisms. If it is clear that the main part of this task falls to the immune cells, recent work shows that neurons can also detect microbes, although the molecules and mechanisms involved are less characterized. In Drosophila, detection of bacteria-derived peptidoglycan by pattern recognition receptors of the peptidoglycan recognition protein (PGRP) family expressed in immune cells triggers nuclear factor-κB (NF-κB)/immune deficiency (IMD)-dependent signaling. We show here that one PGRP protein, called PGRP-LB, is expressed in bitter gustatory neurons of proboscises. In vivo calcium imaging in female flies reveals that the PGRP/IMD pathway is cell-autonomously required in these neurons to transduce the peptidoglycan signal. We finally show that NF-κB/IMD pathway activation in bitter-sensing gustatory neurons influences fly behavior. This demonstrates that a major immune response elicitor and signaling module are required in the peripheral nervous system to sense the presence of bacteria in the environment.SIGNIFICANCE STATEMENT In addition to the classical immune response, eukaryotes rely on neuronally controlled mechanisms to detect microbes and engage in adapted behaviors. However, the mechanisms of microbe detection by the nervous system are poorly understood. Using genetic analysis and calcium imaging, we demonstrate here that bacteria-derived peptidoglycan can activate bitter gustatory neurons. We further show that this response is mediated by the PGRP-LC membrane receptor and downstream components of a noncanonical NF-κB signaling cascade. Activation of this signaling cascade triggers behavior changes. These data demonstrate that bitter-sensing neurons and immune cells share a common detection and signaling module to either trigger the production of antibacterial effectors or to modulate the behavior of flies that are in contact with bacteria. Because peptidoglycan detection doesn't mobilize the known gustatory receptors, it also demonstrates that taste perception is much more complex than anticipated.

How Bacteria Impact Host Nervous System and Behaviors: Lessons from Flies and Worms.

Behavior is the neuronally controlled, voluntary or involuntary response of an organism to its environment. An increasing body of evidence indicates that microbes, which live closely associated with animals or in their immediate surroundings, significantly influence animals' behavior. The extreme complexity of the nervous system of animals, combined with the extraordinary microbial diversity, are two major obstacles to understand, at the molecular level, how microbes modulate animal behavior. In this review, we discuss recent advances in dissecting the impact that bacteria have on the nervous system of two genetically tractable invertebrate models, Drosophila melanogaster and Caenorhabditis elegans.

Peptidoglycan-dependent NF-κB activation in a small subset of brain octopaminergic neurons controls female oviposition.

When facing microbes, animals engage in behaviors that lower the impact of the infection. We previously demonstrated that internal sensing of bacterial peptidoglycan reduces Drosophila female oviposition via NF-κB pathway activation in some neurons (Kurz et al., 2017). Although we showed that the neuromodulator octopamine is implicated, the identity of the involved neurons, as well as the physiological mechanism blocking egg-laying, remained unknown. In this study, we identified few ventral nerve cord and brain octopaminergic neurons expressing an NF-κB pathway component. We functionally demonstrated that NF-κB pathway activation in the brain, but not in the ventral nerve cord octopaminergic neurons, triggers an egg-laying drop in response to infection. Furthermore, we demonstrated via calcium imaging that the activity of these neurons can be directly modulated by peptidoglycan and that these cells do not control other octopamine-dependent behaviors such as female receptivity. This study shows that by sensing peptidoglycan and hence activating NF-κB cascade, a couple of brain neurons modulate a specific octopamine-dependent behavior to adapt female physiology status to their infectious state.

Lipid Catabolism Fuels Drosophila Gut Immunity.

Immune responses and metabolic regulation are tightly coupled in animals, but the underlying mechanistic connections are not fully understood. In this issue of Cell Host & Microbe, Lee et al. (2018) reveal how sustained ROS production in the gut depends on an upstream metabolic switch.

Drosophila larvae food intake cessation following exposure to Erwinia contaminated media requires odor perception, Trpa1 channel and evf virulence factor.

When exposed to microorganisms, animals use several protective strategies. On one hand, as elegantly exemplified in Drosophila melanogaster, the innate immune system recognizes microbial compounds and triggers an antimicrobial response. On the other hand, behaviors preventing an extensive contact with the microbes and thus reducing the risk of infection have been described. However, these reactions ranging from microbes aversion to intestinal transit increase or food intake decrease have been rarely defined at the molecular level. In this study, we set up an experimental system that allowed us to rapidly identify and quantify food intake decreases in Drosophila larvae exposed to media contaminated with bacteria. Specifically, we report a robust dose-dependent food intake decrease following exposure to the bacteria Erwinia carotovora carotovora strain Ecc15. We demonstrate that this response does not require Imd innate immune pathway, but rather the olfactory neuronal circuitry, the Trpa1 receptor and the evf virulence factor. Finally, we show that Ecc15 induce the same behavior in the invasive pest insect Drosophila suzukii.

Amyloidosis in Retinal Neurodegenerative Diseases.

As a part of the central nervous system, the retina may reflect both physiological processes and abnormalities related to pathologies that affect the brain. Amyloidosis due to the accumulation of amyloid-beta (Aß) was initially regarded as a specific and exclusive characteristic of neurodegenerative alterations seen in the brain of Alzheimer's disease (AD) patients. More recently, it was discovered that amyloidosis-related alterations, similar to those seen in the brain of Alzheimer's patients, also occur in the retina. Remarkably, these alterations were identified not only in primary retinal pathologies, such as age-related macular degeneration (AMD) and glaucoma, but also in the retinas of Alzheimer's patients. In this review, we first briefly discuss the biogenesis of Aß, a peptide involved in amyloidosis. We then discuss some pathological aspects (synaptic dysfunction, mitochondrial failure, glial activation, and vascular abnormalities) related to the neurotoxic effects of Aß. We finally highlight common features shared by AD, AMD, and glaucoma in the context of Aß amyloidosis and further discuss why the retina, due to the transparency of the eye, can be considered as a "window" to the brain.