The microbiome shapes host immunity, yet the molecular signals by which specific bacteria modulate innate defenses remain poorly understood. In Caenorhabditis elegans, the Intracellular Pathogen Response (IPR) is a transcriptional program activated by obligate intracellular pathogens and shares features with mammalian type I interferon responses. We aimed to identify microbiome-derived triggers of the IPR and mechanisms of host protection.
We screened twelve native bacterial isolates using an IPR GFP reporter. Reporter activation in different tissues was observed by microscopy, and bacterial inactivation or RNA treatments were used to identify the molecular triggers. Transcriptomic profiling (RNA-seq, qRT-PCR) identified host genes induced by bacterial exposure. Pathogen burden was quantified by FISH, and developmental assays measured fitness effects.
Stenotrophomonas indicatrix (JUb19) robustly activated the IPR in intestine, epidermis, neurons, and somatic gonad despite residing extracellularly, making it the first non-invasive bacterium known to trigger this pathway. Heat-killed bacteria failed to induce the IPR, whereas chemical or mechanical inactivation retained activity, implicating a heat-labile trigger. Bacterial RNA contributed to IPR activation, revealing microbiome RNA as a novel immune signal. Transcriptomic analyses showed induction of IPR genes, lysozymes, and metabolic regulators that enhance resistance to intracellular pathogens, with modest fitness costs. Remarkably, protection was inherited by naïve progeny that had never been exposed to JUb19.
Our findings identify a previously unrecognized extracellular mechanism by which microbiome-derived RNA activates epithelial immunity and provides intergenerational protection in C. elegans, linking commensal bacteria, RNA signaling, and heritable host defense.
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Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)
V. Lažetić, Jordan D. West, Samuel K. Schwartz· Journal of Immunology· 0 citations
Nematodes are ubiquitous metazoans that occupy diverse ecological niches, exposing them to a wide range of viruses and positioning them as both viral hosts and vectors. Free-living nematodes, particularly Caenorhabditis elegans and Caenorhabditis briggsae, provide powerful genetic models for studying antiviral immune mechanisms. Natural infections with noda-like viruses have revealed powerful antiviral defense strategies in Caenorhabditis species, including RNA interference, the Intracellular Pathogen Response, Signal Transducers and Activators of Transcription (STAT)-like transcriptional regulation, terminal RNA uridylation, and structural barriers to viral entry and egress. These mechanisms demonstrate robust antiviral mechanisms independent of canonical interferon signaling while relying on conserved principles of viral RNA recognition, signal amplification, and coordinated transcriptional responses. Beyond free-living species, parasitic nematodes harbor a diverse and largely unexplored virome. Plant-parasitic nematodes host multiple RNA viruses and act as vectors for economically and agriculturally important plant pathogens, while animal-parasitic nematodes carry persistent viral infections that may influence the immune responses and disease outcomes of their animal hosts. Evidence for functional antiviral RNA interference in parasitic nematodes suggests partial conservation of immune mechanisms, although functional data remain limited. Together, these findings define current knowledge of viral infections and antiviral responses in nematodes and emphasize the need for deeper mechanistic studies, particularly in parasitic species, where the molecular basis of viral recognition and immune defense remains poorly characterized.
Dustin T. Howard, V. Lažetić· Frontiers in Bioscience· 0 citations
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