A Nutrition-Longevity Tradeoff Enforced by Innate Immunity.

Dietary restriction (DR) extends lifespan in multiple animal species, but the underlying molecular mechanisms remain poorly understood. A recent study published in Cell Metabolism by Wu et al. (2019) shows that DR represses an evolutionarily conserved p38 MAPK pathway involved in innate immunity, leading to diminished expression of p38 MAPK-regulated genes and extended lifespan.

C. elegans orphan nuclear receptor NHR-42 represses innate immunity and promotes lipid loss downstream of HLH-30/TFEB.

In recent years, transcription factors of the Microphthalmia-TFE (MiT) family, including TFEB and TFE3 in mammals and HLH-30 in Caenorhabditis elegans, have emerged as important regulators of innate immunity and inflammation in invertebrates and vertebrates. Despite great strides in knowledge, the mechanisms that mediate downstream actions of MiT transcription factors in the context of innate host defense remain poorly understood. Here, we report that HLH-30, which promotes lipid droplet mobilization and host defense, induces the expression of orphan nuclear receptor NHR-42 during infection with Staphylococcus aureus. Remarkably, NHR-42 loss of function promoted host infection resistance, genetically defining NHR-42 as an HLH-30-controlled negative regulator of innate immunity. During infection, NHR-42 was required for lipid droplet loss, suggesting that it is an important effector of HLH-30 in lipid immunometabolism. Moreover, transcriptional profiling of nhr-42 mutants revealed wholesale activation of an antimicrobial signature, of which abf-2, cnc-2, and lec-11 were important for the enhanced survival of infection of nhr-42 mutants. These results advance our knowledge of the mechanisms by which MiT transcription factors promote host defense, and by analogy suggest that TFEB and TFE3 may similarly promote host defense via NHR-42-homologous nuclear receptors in mammals.

A unifying hypothesis on the central role of reactive oxygen species in bacterial pathogenesis and host defense in C. elegans.

During intestinal infection, microbes induce ROS by various mechanisms in C. elegans. ROS can have beneficial roles, acting as antimicrobials and as signaling molecules that activate cytoprotective pathways. Failure to maintain appropriate levels of ROS causes oxidative stress and cellular damage. This review uses the Damage Response Framework to interpret several recent observations on the relationships between infection, host response, and host damage, with a focus on mechanisms mediated by ROS. We propose a unifying hypothesis that ROS drive a collapse in proteostasis in infected C. elegans, which results in death during unresolved infection. Because the signaling pathways highlighted here are conserved in mammals, the mentioned and future studies can provide new tools of hypothesis generation in human health and disease.

NHR-49/PPAR-α and HLH-30/TFEB cooperate for C. elegans host defense via a flavin-containing monooxygenase.

The model organism Caenorhabditis elegans mounts transcriptional defense responses against intestinal bacterial infections that elicit overlapping starvation and infection responses, the regulation of which is not well understood. Direct comparison of C. elegans that were starved or infected with Staphylococcus aureus revealed a large infection-specific transcriptional signature, which was almost completely abrogated by deletion of transcription factor hlh-30/TFEB, except for six genes including a flavin-containing monooxygenase (FMO) gene, fmo-2/FMO5. Deletion of fmo-2/FMO5 severely compromised infection survival, thus identifying the first FMO with innate immunity functions in animals. Moreover, fmo-2/FMO5 induction required the nuclear hormone receptor, NHR-49/PPAR-α, which controlled host defense cell non-autonomously. These findings reveal an infection-specific host response to S. aureus, identify HLH-30/TFEB as its main regulator, reveal FMOs as important innate immunity effectors in animals, and identify the mechanism of FMO regulation through NHR-49/PPAR-α during S. aureus infection, with implications for host defense and inflammation in higher organisms.

Nervous system control of intestinal host defense in C. elegans.

Interplay between the nervous and immune systems is critical for homeostasis, and its dysfunction underlies pathologies such as multiple sclerosis, autism, leukemia, and inflammation. The nematode Caenorhabditis elegans provides an opportunity to define evolutionarily conserved mechanisms of regulation of host innate immunity and inflammation in a genetically tractable whole-animal system. In the past few years, the C. elegans nervous system has emerged as an integral part of host defense against pathogens, acting through diverse mechanisms to repress or induce protective transcriptional responses to infection in distal tissues. In this review, we discuss current knowledge of the mechanisms through which the C. elegans nervous system controls the expression of host defense genes in the intestinal epithelium. Although still incomplete, the insights derived from such work have broad implications for neural regulation of epithelial function at mucosal barriers in higher organisms in health and disease.