Neural control of behavioral and molecular defenses in C. elegans

https://doi.org/10.1016/j.conb.2019.10.012Get rights and content

Highlights

  • Neural circuits regulate immune pathways in non-nervous tissues.

  • Neural circuits control behavioral and molecular immunity in C. elegans.

  • Conserved neuromodulators inhibit or activate immune responses in C. elegans.

The nervous and immune systems use bi-directional communication to control host responses against microbial pathogens. Recent studies at the interface of the two systems have highlighted important roles of the nervous system in the regulation of both microbicidal pathways and pathogen avoidance behaviors. Studies on the neural circuits in the simple model host Caenorhabditis elegans have significantly improved our understanding of the roles of conserved neural mechanisms in controlling innate immunity. Moreover, behavioral studies have advanced our understanding of how the nervous system may sense potential pathogens and consequently elicit pathogen avoidance, reducing the risk of infection. In this review, we discuss the neural circuits that regulate both behavioral immunity and molecular immunity in C. elegans.

Introduction

Metazoans have developed multiple strategies to deal with pathogenic microbes, including pathogen avoidance, resistance, and tolerance [1]. Different animals, ranging from simple nematodes to chimpanzees and humans, engage in many behaviors that reduce their exposure to pathogens [2, 3, 4]. These avoidance behaviors that protect against pathogen infections are referred to as the behavioral immune system [5]. In addition, microbial sensing mechanisms activate molecular immune pathways that provide resistance to pathogens by reducing pathogen burden and clearing the infection. Increasing evidence also indicates that those mechanisms involved in the initial activation of defense pathways also regulate the immune system. Thus, immune regulatory mechanisms play an important role in maintaining immune homeostasis because disproportionate activation of immune pathways could be detrimental to the host.

The nervous system maintains control of homeostasis through bi-directional communication with peripheral physiological systems. Recent research at the interface of the nervous system and the immune system identified neural circuits that are triggered by and control immune pathways [6, 7, 8, 9, 10]. While the understanding of neuro-immune communications holds great therapeutic potential [11], the complex nervous and immune systems of higher organisms have limited our understanding of these connections. Studies in the model nematode Caenorhabditis elegans have advanced our understanding of neuro-immune connections. In this review, we describe these recent advances in C. elegans.

Section snippets

Neural circuits involved in behavioral immunity

Physical avoidance of pathogens is a vital defense strategy used by hosts to reduce pathogen infections [2,4]. In mammals, olfactory chemosensory neurons and nociceptor sensory neurons detect various bacterial products, such as toxins, quorum-sensing molecules, formyl peptides, and lipopolysaccharides, through distinct molecular mechanisms that lead to rapid avoidance behaviors [6,12, 13, 14, 15, 16]. Similarly, in the fruit fly Drosophila melanogaster, olfactory and gustatory neurons have been

Neural regulation of molecular immunity

While the activities of immune pathways reduce pathogen burden and are important to resist infections, uncontrolled activation of immune pathways could be detrimental to the host. Therefore, activation of the immune system must be controlled to minimize the changes in organismal homeostasis that occur during the host’s response to pathogen attack. The nervous system of C. elegans seems to play an important role during the host response to infections as it can both activate and suppress the

Neural activation of immune pathways

Neural circuits that activate immune pathways in different tissues have been identified in C. elegans and are involved in defense responses against different pathogenic microbes. Infections of the fungus Drechmeria coniospora lead to increased production of antimicrobial peptides of the Caenacin family in the epidermis of C. elegans. The expression of caenacin genes is controlled by the neural TGF-β analog DBL-1 via its receptor SMA-6 and the cytosolic Smad SMA-3 in hypodermis [46]. In addition

Neural suppression of immune pathways

Several neural circuits have been identified that suppress immune pathways in C. elegans. Animals defective in neural secretion, such as unc-13 and unc-31 mutants, were more resistant to P. aeruginosa infection [54]. This suggested that the nervous system secretes cues that are immunoinhibitory. Indeed, treatments that resulted in a sustained increase in neural secretion increased sensitivity to pathogens. One of the immunoinhibitory cues that is released by neurons is the insulin-like peptide

Intersection of behavioral and molecular immune regulation

Several neural regulators that control molecular immunity also modulate avoidance behavior. For example, NPR-1 in the AQR, PQR, and URX neurons not only regulates innate immunity but also controls the avoidance behavior [22,38]. Similarly, DBL-1 controls both of these defense responses via a single circuit involving the TGF-β receptor SMA-6 and the cytoplasmic Smad SMA-3 in the hypodermis [32,46]. The modulation of both molecular immunity and avoidance behavior by the same neural circuits could

Conclusion and future perspectives

Studies on the neural control of immunity in C. elegans have greatly improved our understanding of conserved neuro-immune connections. The roles of several conserved neurotransmitters such as serotonin, dopamine, octopamine, and acetylcholine in regulating immunity have been described. In addition, the roles of different TGF-β pathways as well as conserved neuropeptides in controlling immunity have been delineated. Despite these advances, it is still not understood if and how the neural

Conflict of interest statement

Nothing declared.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgement

Work in the Aballay laboratory is funded by the N.I.H. (grants GM070977 and AI117911, www.nigms.nih.gov).

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