The immune system is often viewed as a sophisticated defence network that detects invading microbes. However, new research suggests that cells can also protect themselves by monitoring the health of their own internal machinery. A study by researchers at the Indian Institute of Science Education and Research (IISER), Mohali, has found that disruption of a normal RNA processing pathway can itself act as a danger signal, triggering protective immunity in the roundworm Caenorhabditis elegans.

The findings, published in PLOS Pathogens, offer fresh insight into how animals may have evolved to recognise infection beyond simply detecting microbial molecules.

The idea echoes the Red Queen Hypothesis, proposed by evolutionary biologist Leigh Van Valen and inspired by Lewis Carroll’s Through the Looking-Glass: hosts and pathogens are locked in a perpetual evolutionary race, with each continually adapting to keep pace with the other. While pathogens evolve strategies to evade immune detection, hosts develop increasingly sophisticated surveillance systems to identify infection.

Many disease-causing microbes interfere with fundamental cellular processes to promote their own survival. This prompted the IISER Mohali team, led by Dr. Jogender Singh and Ms. Annesha Ghosh, to ask whether disturbances in normal cellular functions could themselves serve as warning signals that activate immunity.

To investigate this, the researchers used a genetically engineered strain of C. elegans carrying a fluorescent reporter that glows when innate immune responses are activated. They introduced random mutations across the worm’s genome and screened for animals showing elevated immune activity.

The search proved difficult. Many mutants exhibited severe developmental abnormalities, sterility, or poor survival, underscoring the delicate balance between immunity and normal growth. Eventually, the team identified a viable mutant carrying a loss-of-function mutation in a gene encoding an RNA cap methyltransferase.

The mutant worms displayed significantly improved resistance to bacterial infection, surviving longer and clearing pathogens more efficiently than normal worms.

RNA cap methyltransferases are already known in mammals for their role in distinguishing the cell’s own methylated RNA from unmethylated viral RNA, thereby contributing to antiviral defence. Their role in antibacterial immunity, however, had remained largely unexplored.

The study shows that disruption of RNA processing itself can function as an internal stress signal that activates innate immune responses.

To understand the underlying mechanism, the researchers analysed global gene expression in the mutant worms. They found widespread activation of immune-related genes alongside reduced expression of genes involved in protein synthesis.

This finding was particularly intriguing because many pathogens suppress host protein synthesis during infection, and cells possess surveillance pathways that detect such disruptions. Surprisingly, the transcription factor previously known to regulate immunity under protein synthesis stress was not required in these mutants.

Instead, a comprehensive reverse genetic screen identified a different intestinal transcription factor that proved essential for immune activation following disruption of RNA processing.

The researchers then asked whether the RNA processing defect resembled a genuine infection. They found that all immune genes activated in the mutant worms were also induced during bacterial infection. Furthermore, the same intestinal transcription factor regulated immune responses both in mutant animals and in infected worms.

Together, these observations suggest that defects in RNA processing mimic important features of infection, activating an evolutionarily conserved immune programme that enhances host defence.

“Rather than sensing only invading microbes, cells can also monitor the integrity of their own essential processes. Our findings identify RNA processing as one such surveillance mechanism that helps activate protective immunity,” said Dr. Jogender Singh, who led the study.

Commenting independently on the findings, Dr. Ajit Chande of IISER Bhopal said the work strengthens growing evidence that RNA quality control serves as an immune sensor across evolution.

“Mammalian viruses are well known to hijack core RNA processing and translation pathways to support their replication. The recent C. elegans study from the Singh laboratory suggests that this vulnerability is also exploited by the host as a conserved axis of immune surveillance in bacterial infection,” he said.

According to Dr. Chande, complementary studies in mammalian systems have shown that disruption of RNA capping can itself act as an antiviral signal, supporting the broader concept that hosts interpret abnormalities in RNA processing as indicators of pathogenic threat rather than routine cellular disturbances.

Beyond infection biology, the findings could have wider implications. Disruptions in RNA metabolism, protein synthesis and cellular homeostasis are also associated with ageing and several human disorders, including neurodegenerative diseases. Understanding how cells detect these internal disturbances may therefore reveal new principles of immune surveillance and eventually inform therapeutic approaches for immune-related diseases.