Angiostrongylus cantonensis is best known as the rat lungworm, a nematode whose natural life cycle cycles between rats and snails or slugs. Humans become accidental, non-permissive hosts when they consume raw or undercooked snails, contaminated vegetables, or sometimes even slime trails left on produce. In people, the third-stage larvae cannot complete their development, but they do something arguably worse: they migrate to the central nervous system, where they cause eosinophilic meningitis, severe headaches, neurological damage, and in serious cases death. There is no universally effective therapy, and the standard anthelmintic drug albendazole, which kills the worms, does little on its own to quiet the inflammatory storm their presence provokes in brain tissue.

The new study focuses on a molecular player with a long history in inflammatory disease research: the receptor for advanced glycosylation end products, better known as RAGE. RAGE is a multi-ligand receptor sitting on cell surfaces that binds a remarkably broad range of danger-associated molecules, including members of the S100 protein family such as S100B, high mobility group box 1, amyloid beta, and advanced glycation end products. Once engaged, RAGE activates signaling cascades, most famously the nuclear factor-kappa B pathway, that crank up production of inflammatory mediators. RAGE has been extensively implicated in chronic diseases, including Alzheimer’s disease and diabetic complications, but its role in parasitic infections of the brain had remained largely unexplored territory.

Working with mice infected with A. cantonensis, the researchers found that infection drove RAGE expression sharply upward in the brain. Alongside this rise, they measured a cascade of familiar inflammatory fingerprints: elevated levels of tumor necrosis factor-alpha, interleukin-1 beta, interleukin-17A, cyclooxygenase-2, and activated NF-kappa B, together with increased production of reactive oxygen species and superoxide, the chemically reactive molecules that damage cells and tissues. The blood-brain barrier, the tightly sealed endothelial gatekeeper that normally shields the central nervous system from circulating blood components, also became measurably more permeable, a change that both reflects and enables the inflammatory assault on neural tissue. Larval recovery counts confirmed that the parasites had established themselves in the infected animals’ brains.

But the team was not only tracking a pro-inflammatory receptor. They were also following a brake on it. MicroRNAs are short, non-coding RNA molecules that fine-tune gene expression after transcription, and previous work had shown that inhibiting miR-185-3p leads to downregulation of RAGE. In the infected mice, the researchers observed the opposite pattern of what one might naively expect: levels of miR-185-3p dropped during infection, precisely when RAGE was climbing. This inverse relationship pointed to a regulatory axis in which the loss of this microRNA removes a natural restraint on RAGE-driven inflammation, allowing the neuroinflammatory response to escalate unchecked.

To test whether this axis could be therapeutically manipulated, the team deployed three interventions in infected mice: Azeliragon, a known RAGE antagonist that has been studied in the context of Alzheimer’s disease; a synthetic miR-185-3p mimic designed to restore the microRNA’s levels; and a negative control mimic with no intended activity. They also crossed these interventions with albendazole, the standard anthelmintic, creating combination treatment groups. The experimental toolkit was comprehensive: larval recovery assays to count surviving worms, blood-brain barrier permeability tests, Western blotting and enzyme-linked immunosorbent assays to quantify proteins and cytokines, reactive oxygen species detection, quantitative real-time polymerase chain reaction for gene expression, and hematoxylin and eosin staining to visualize tissue damage under the microscope.

The results were striking. In every treated group, including mice given albendazole alone, larval recovery, blood-brain barrier permeability, and inflammatory mediator levels all fell relative to untreated infected controls. But the combination therapies stood out. Mice receiving albendazole together with either Azeliragon or the miR-185-3p mimic showed the greatest reductions across the board, suggesting that calming the RAGE-driven inflammatory response does more than soothe symptoms; it appears to make the anthelmintic treatment itself more effective. The negative control mimic, by contrast, did not reproduce these benefits, reinforcing that the effect was specific to restoring miR-185-3p function rather than a generic consequence of delivering RNA molecules.

The mechanistic logic behind this synergy is worth unpacking. Albendazole kills parasites, but dying and migrating larvae within brain tissue continue to release antigens and damage-associated molecular patterns that feed the RAGE signaling loop. By blocking RAGE with Azeliragon, or by replenishing the microRNA that restrains RAGE expression, the combination therapy simultaneously reduces the inflammatory amplification that turns a worm infection into a neurological crisis. Lower levels of tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-17A mean less recruitment and activation of inflammatory cells, less oxidative damage from reactive oxygen species, and better preservation of the blood-brain barrier. In this view, the RAGE/miR-185-3p axis functions as a master regulator of how violently the brain responds to the parasite’s presence.

The clinical implications are significant, though the path from mice to medicine requires the usual caution. Azeliragon has already been through human safety testing in Alzheimer’s disease trials, which could accelerate its repurposing for parasitic meningitis if the findings translate. MicroRNA-based therapies face greater delivery challenges, particularly across the blood-brain barrier, but the demonstration that a single microRNA mimic can meaningfully alter the course of a parasitic brain infection adds weight to the growing field of RNA therapeutics for neurological disease. For a condition that currently lacks a definitive treatment and that continues to cause outbreaks linked to raw snail consumption in parts of Asia and the Pacific, the prospect of an add-on therapy that protects the brain while the anthelmintic clears the worms represents a genuinely new therapeutic direction.

The research, led by Chii-Wen Chou and Chang-Sheng Lin with corresponding author Cheng-You Lu and colleagues across institutions including National Chung Hsing University, Chung Shan Medical University, and Tungs’ Taichung MetroHarbor Hospital, was supported by grants from Taiwanese hospital and national science funding bodies and conducted under approved animal care protocols. The authors emphasize that RAGE and miR-185-3p play important regulatory roles in the neuroinflammatory response associated with angiostrongyliasis, and that combining an anthelmintic agent with a RAGE-targeting intervention enhances treatment efficacy while delivering additive anti-inflammatory effects that attenuate parasite-induced brain injury. As food-borne parasitic diseases continue to emerge in new regions through global trade and changing culinary habits, strategies that target the host’s own inflammatory machinery, rather than the parasite alone, may prove to be the most durable weapons in the arsenal.

Subject of Research: The role of the RAGE/miR-185-3p axis in Angiostrongylus cantonensis-induced neuroinflammation and enhanced anthelmintic therapy

Article Title: Targeting the RAGE/miR-185-3p axis enhances anthelmintic therapy and attenuates Angiostrongylus cantonensis–induced neuroinflammation

Article References: Chou, C.-W., Lin, C.-S., Tseng, C.-Y., Chen, K.-M., Chen, W.-J., Lai, S.-C., Liu, W.-T., Hsu, C.-H., Chang, Y.-K., Huang, Y.-H., Chiu, C.-H., & Lu, C.-Y. (2026). Targeting the RAGE/miR-185-3p axis enhances anthelmintic therapy and attenuates Angiostrongylus cantonensis–induced neuroinflammation. Parasites & Vectors. https://doi.org/10.1186/s13071-026-07632-6

Image Credits: AI Generated

DOI: 10.1186/s13071-026-07632-6

Keywords: Angiostrongylus cantonensis, rat lungworm, RAGE, miR-185-3p, neuroinflammation, parasitic meningitis, albendazole, Azeliragon, blood-brain barrier, microRNA, eosinophilic meningitis, anthelmintic therapy

The parasite behind the disease has an unusual life cycle that explains why humans become accidental and unfortunate hosts. Adult worms live in the pulmonary arteries of rats, where they lay eggs that hatch into first-stage larvae. These larvae are expelled in rat faeces, then ingested by snails and slugs, which act as intermediate hosts. Within those molluscs, the larvae develop into third-stage larvae, the infectious form for humans. People typically acquire the infection by eating raw or undercooked snails, slugs, or contaminated fresh produce, or sometimes by consuming paratenic hosts such as freshwater prawns or crabs that have carried the larvae without supporting their development. Once ingested, the larvae penetrate the intestinal wall, enter the bloodstream and migrate to the central nervous system, where they die in the brain and spinal cord and trigger a fierce inflammatory response.

That inflammatory response is what defines the disease clinically. Unlike bacterial meningitis, which is dominated by neutrophils, or viral meningitis, which is dominated by lymphocytes, neuroangiostrongyliasis produces a striking influx of eosinophils, the white blood cells best known for fighting parasites and mediating allergic disease. Eosinophilic pleocytosis in the cerebrospinal fluid has long been considered the diagnostic signature of the infection, and it underpins most case definitions used in endemic regions. The headache that brings patients to hospital is typically severe and unrelenting, often accompanied by neck stiffness, and in more severe cases the migrating larvae and the inflammation they provoke can cause focal neurological deficits, paralysis, or death. There is no universally validated rapid diagnostic test in most endemic settings, and molecular confirmation by polymerase chain reaction remains unavailable in many hospitals where the disease is most common.

The Hanoi team, led by Tra Thu Doan of the Institute for Tropical Medicine at Bach Mai Hospital, assembled their series using a composite case definition. Patients had to show clinical meningitis, eosinophilia in the peripheral blood or the cerebrospinal fluid, and a reactive serum enzyme-linked immunosorbent assay for antibodies specific to A. cantonensis, with alternative diagnoses excluded. During the study period, the hospital lacked the capacity to confirm the parasite by cerebrospinal fluid polymerase chain reaction, and no patient in the series met a definite standard based on recovery of larvae or molecular detection. That limitation matters, and the authors are explicit about it: their findings describe probable cases, and the proportions they report are conditioned on the sensitivity of the case definition and of routine laboratory differentials.

The demographic and clinical profile of the 30 patients is instructive. Their mean age was 39.2 years, with a standard deviation of 17.1, and just over half, 16 of 30, were men. More than half, 17 patients, came from Nghe An or Thanh Hoa, two north-central provinces that appear to be hotspots for exposure. Headache was universal, present in all 30 patients, and neck stiffness occurred in 25, or 83.3 percent. Eleven patients, 36.7 percent, presented with focal neurological deficits, a reminder that the disease is not always a benign self-limiting headache syndrome. Exposure histories were abstracted retrospectively from routine admission notes, so the authors caution that they cannot identify a specific transmission route, though the geographic clustering points to where future surveillance should concentrate.

The laboratory findings reveal the diagnostic subtlety at the heart of the paper. Peripheral blood eosinophilia, defined as more than 8 percent eosinophils, was present in 19 of 30 patients, or 63.3 percent. But the most striking figure concerns the cerebrospinal fluid: in six patients, 20 percent of the series, no eosinophils at all were recorded on the routine differential at presentation. The authors report a 95 percent confidence interval of 9.5 to 37.3 percent for that proportion, and their conclusion is unambiguous. A normal or lymphocyte-predominant cerebrospinal fluid differential at presentation should not exclude neuroangiostrongyliasis in a patient with compatible symptoms and reactive serology. The finding echoes earlier work from northern Vietnam, including a 2020 study in PLoS Neglected Tropical Diseases that described meningitis patients with confirmed A. cantonensis infection who lacked cerebrospinal fluid eosinophilia.

Other cerebrospinal fluid parameters painted a picture of a disease that is inflammatory but rarely metabolic in the way tuberculosis meningitis can be. Hypoglycorrhachia, a low cerebrospinal fluid glucose below 2.2 millimoles per litre, was uncommon, seen in only five patients, 16.7 percent. Low cerebrospinal fluid chloride, below 120 millimoles per litre, was more frequent, present in 13 of 30 patients, or 43.3 percent, a finding that could mislead clinicians toward a diagnosis of tuberculous meningitis if interpreted in isolation. Perhaps the most encouraging laboratory trend was temporal: across serial lumbar punctures, cerebrospinal fluid cell counts, eosinophil percentages and protein levels all fell progressively, providing an objective measure of recovery that clinicians can track over the course of treatment.

Treatment in the series followed a combined approach. Every patient received albendazole, an anthelminthic drug that kills the larvae, together with methylprednisolone, a corticosteroid intended to dampen the inflammatory reaction triggered by dying parasites. This combination reflects international guidelines updated in 2021, which recommend concurrent corticosteroids with anthelminthic therapy on the theory that killing larvae without suppressing inflammation can paradoxically worsen symptoms. The outcomes were broadly favourable: 26 of 30 patients, 86.7 percent, recovered fully, three patients, 10 percent, relapsed within a six-month follow-up window, and none died. No serious adverse event was attributed to either drug. The authors are careful, however, to note that without a comparator group, no inference can be drawn about the independent contribution of either albendazole or methylprednisolone to those outcomes, a caveat that applies to virtually all published treatment data in this field.

The study’s limitations are those inherent to any retrospective case series. The case definition admits patients on peripheral eosinophilia with reactive serology alone, and the sensitivity of a routine clinical differential is imperfect, so the 20 percent figure for absent cerebrospinal fluid eosinophils is best understood as a property of this cohort and its methods rather than a universal constant. Serological tests for A. cantonensis vary in specificity, and cross-reactivity with other parasitic infections remains a concern in endemic settings. Exposure histories recorded in routine notes are a blunt instrument for epidemiology. Yet the clinical signal is consistent with a growing body of evidence from across the region, including a 2017 study in Clinical Infectious Diseases that established A. cantonensis as an important cause of eosinophilic meningitis in southern Vietnam and molecular confirmations of the parasite in cerebrospinal fluid from Laos.

For clinicians working in Vietnam and neighbouring countries, the practical messages are concrete. Neuroangiostrongyliasis should be considered in any patient with subacute severe headache and meningism, particularly when focal deficits are present, even if the cerebrospinal fluid differential shows no eosinophils on first examination. Repeat lumbar puncture may reveal the characteristic eosinophilic pleocytosis as the disease evolves, and serial measurements offer a way to monitor response. For public health authorities, the concentration of cases from Nghe An and Thanh Hoa argues for prospective surveillance and investment in molecular diagnostic capacity in the north-central provinces, where the ecological conditions that sustain the parasite, invasive Pomacea snails among them, are well documented. As the rat lungworm continues its global spread, documented as far afield as Brazil and Hawaii, the Vietnamese series adds an important data point: the disease is present, treatable, and easier to miss than its textbook description suggests.

Subject of Research: Human neuroangiostrongyliasis caused by Angiostrongylus cantonensis in northern Vietnam

Article Title: Human Neuroangiostrongyliasis Caused by Angiostrongylus cantonensis in Northern Vietnam: a Clinical–Epidemiological Case Series of Eosinophilic Response and Disease Manifestations

Article References: Thu Doan, T., Khanh Thi Nguyen, L., Minh Nong, V., Phuong Thi Ngo, N., Van Do, T., Xuan Dao, C., Xuan Do, C., & Van Vu, G. (2026). Human Neuroangiostrongyliasis Caused by Angiostrongylus cantonensis in Northern Vietnam: a Clinical–Epidemiological Case Series of Eosinophilic Response and Disease Manifestations. Acta Parasitologica, 71(5), Article 222. https://doi.org/10.1007/s11686-026-01412-z

Image Credits: AI Generated

DOI: 10.1007/s11686-026-01412-z

Keywords: Angiostrongylus cantonensis, neuroangiostrongyliasis, eosinophilic meningitis, rat lungworm, Vietnam, eosinophils, cerebrospinal fluid, albendazole, methylprednisolone, case series, parasitic disease, tropical medicine