The research focuses on a family of CD4-positive helper T cells known as Th17 cells, which have occupied an ambiguous position in cystic fibrosis immunology for over a decade. Elevated levels of interleukin-17, the signature cytokine of this lineage, were initially interpreted as a hallmark of pathology, since IL-17 drives neutrophil recruitment and tissue-destructive inflammation. Later work complicated that picture by showing that Th17 cells are functionally heterogeneous. Conventional Th17 cells, which co-produce IL-17 alongside the anti-inflammatory cytokine IL-10 and the epithelial-supporting IL-22, actually promote mucosal homeostasis and barrier integrity. By contrast, a distinct pro-inflammatory population, termed Th1/17 for its co-expression of interferon-gamma and IL-17 in the absence of IL-10, has been implicated in chronic inflammatory diseases ranging from multiple sclerosis to Crohn’s disease. Which of these faces Th17 presents in the cystic fibrosis lung remained an open question.

To resolve it, the team analysed T cells isolated from explanted lungs and blood of people with cystic fibrosis, alongside non-CF lung tissue and healthy donor blood. Using high-dimensional flow cytometry and unsupervised clustering based on chemokine receptor expression, they identified two pathogenic subsets, CCR5-positive Th1/17 cells and pro-inflammatory CCR5-positive Th17 cells, that were markedly enriched in cystic fibrosis lungs compared with both patient blood and non-CF lungs. Critically, this enrichment was not a general feature of the disease. The pathogenic subsets expanded selectively in lungs chronically colonized by Pseudomonas aeruginosa, irrespective of whether other pathogens such as Staphylococcus aureus were also present. In Pseudomonas-negative patients, protective conventional Th17 cells predominated instead, pointing to the bacterium itself as the upstream driver of the pathological shift.

The functional consequences of this shift were striking. In an air-liquid interface model of primary human bronchial epithelium, a laboratory system that recapitulates the differentiated, ciliated airway lining, activated Th1/17 and pro-inflammatory Th17 cells caused extensive disruption of epithelial integrity. Immunofluorescence staining for zonula occludens-1, a core component of tight junctions, revealed discontinuous, fragmented junctional patterns in cultures exposed to these subsets, while conventional Th17 cells left the barrier largely intact. Quantitative artificial intelligence-assisted image analysis confirmed the selective loss of junctional continuity. The pathogenic subsets also provoked a significantly stronger inflammatory response from epithelial cells, which released elevated amounts of cytokines and chemokines including IL-8, IL-6, CCL20 and RANTES, molecules that in turn recruit further immune cells to the airway wall.

Transcriptomic profiling by RNA sequencing deepened the picture. Pulmonary Th1/17 and pro-inflammatory Th17 cells from Pseudomonas-infected cystic fibrosis lungs displayed a distinctive signature of 210 upregulated and 40 downregulated genes compared with the same subsets in blood and non-CF lungs. Gene set enrichment analysis showed that lung-resident pathogenic cells upregulated 21 pathways linked to bacterial response, inflammation and tissue remodelling, with high-ranking genes including PPARG, CEBPD and IRAK2, transcriptional regulators known to shape Th17 differentiation and function. Peripheral counterparts of the same subsets showed a largely repressed programme, indicating that the lung environment itself actively reconfigures these cells rather than merely recruiting pre-formed effectors from the circulation.

T cell receptor sequencing added a crucial layer of evidence. The researchers found a significant expansion of private clonotypes, receptor sequences unique to individual patients, within cystic fibrosis lungs, accounting for 45.8 percent of the Th1/17 repertoire compared with roughly 22 percent in non-CF lungs. Among the most expanded clonotypes, some were shared between Th1/17 and pro-inflammatory Th17 cells but minimally represented in Th1 or conventional Th17 populations, suggesting a common antigenic experience driving functional convergence. Partial overlap between the receptor repertoires of pathogenic subsets and conventional Th17 cells, but not Th1 cells, provided a molecular fingerprint of lineage relationships that the team then tested experimentally.

That experimental work centred on dendritic cells, the antigen-presenting sentinels that instruct T cell fate. The team exposed human monocyte-derived dendritic cells to 26 clinical Pseudomonas aeruginosa strains isolated longitudinally from Danish cystic fibrosis patients, spanning early isolates taken at disease onset and late isolates collected after years of chronic colonization. Late strains were internalized more efficiently and persisted longer inside dendritic cells than the reference laboratory strain PAO1. More importantly, clinical isolates skewed the dendritic cell cytokine output toward a polarizing cocktail of IL-1β and IL-23, the two cytokines known to drive interferon-gamma-producing Th17 differentiation, while relatively suppressing IL-12, the canonical Th1-polarizing signal. IL-1β secretion correlated with intracellular bacterial persistence, and clinical strains also triggered strong release of CCL20, the chemokine that recruits CCR6-positive Th17 cells to sites of infection.

In antigen-specific co-culture assays, the researchers then demonstrated that conventional Th17 cells, not Th1 cells, are the precursors of the pathogenic populations. After ten days of co-culture with Pseudomonas-infected dendritic cells, sorted conventional Th17 cells acquired robust interferon-gamma and IL-17 co-expression, whereas Th1 cells never converted. Unexpectedly, early clinical isolates lacking the classic adaptations of chronic infection, such as reduced motility and biofilm formation, were at least as effective as late isolates at inducing this conversion, and some strains exceeded the levels seen with PAO1. The reprogramming extended to transcription factors: converted cells upregulated C/EBPδ and PPARγ, and in some cases BATF3, mirroring the profile of lung-resident pathogenic Th17 cells from patients. This indicates that the immunostimulatory virulence determinants responsible are present from the earliest stages of colonization and retained throughout bacterial adaptation to the cystic fibrosis lung.

The study thereby rewrites a long-standing paradigm. Adaptive immune dysfunction in cystic fibrosis was widely assumed to emerge only in late-stage disease, but the new data show that Pseudomonas aeruginosa can corrupt protective Th17 immunity from the moment it establishes infection, creating a self-sustaining immunopathological loop in which reprogrammed T cells damage the epithelium, epithelial cells release chemokines that recruit more Th17 cells, and the resulting inflammation further impairs bacterial clearance. The findings carry direct therapeutic implications. IL-1 receptor blockade with anakinra has already been shown to mitigate Pseudomonas-driven airway inflammation in cystic fibrosis, and IL-23 inhibitors are clinically established in other chronic inflammatory diseases, although safety concerns about prolonged IL-1β blockade and the need to preserve protective mucosal immunity remain. The authors caution that their lung cohort reflects advanced disease and that the specific bacterial or host antigens driving the T cell skewing are still unknown. Even so, selectively depleting Th1/17 and pro-inflammatory Th17 cells, or blocking their generation from conventional Th17 precursors, now stands as a credible precision immunomodulatory strategy, one that could address the inflammation that persists even in patients receiving CFTR modulator therapy.

Subject of Research: Pseudomonas aeruginosa-driven reprogramming of Th17 cells in cystic fibrosis lung immunopathology

Article Title: Pseudomonas aeruginosa induces the generation of pathogenic IFNγ+Th17 cells that promote lung damage and chronic inflammation in cystic fibrosis

Article References: Dusetti, I., Conte, G., Chiara, M., Puccio, S., Guidone, D., Ricciardelli, E., Cibella, J., Ronzio, M., Dolfini, D., Rossi, E., Landini, P., Ascagni, M., Orlandi, R., Damarco, F., Palleschi, A., Gramegna, A., Blasi, F., Lugli, E., Galietta, L. J., … Paroni, M. (2026). Pseudomonas aeruginosa induces the generation of pathogenic IFNγ+Th17 cells that promote lung damage and chronic inflammation in cystic fibrosis. Nature Microbiology. https://doi.org/10.1038/s41564-026-02469-2

Image Credits: AI Generated

DOI: 10.1038/s41564-026-02469-2

Keywords: cystic fibrosis, Pseudomonas aeruginosa, Th17 cells, interferon-gamma, dendritic cells, IL-23, IL-1β, epithelial barrier, T cell receptor, mucosal immunity, chronic inflammation, immunotherapy

In classical medicine, ileus referred to a violent, often fatal condition of the abdomen in which the intestines were believed to be gripped by pain and dysfunction. Ancient and early modern physicians used the term for what they described as intestinal colic or a twisting suffering of the gut, a syndrome recognized by severe abdominal distension, vomiting, and collapse. The word carried an aura of dread. For centuries, ileus was less an anatomical diagnosis than a description of a catastrophic clinical picture, one that physicians could observe but rarely explain and almost never treat.

As Ballantyne documented in a 1984 review of the term’s changing definition over three millennia, the modern era brought a decisive shift. By the nineteenth and early twentieth centuries, surgeons increasingly distinguished between mechanical obstruction of the bowel, in which a physical blockage halts the passage of intestinal contents, and paralytic or adynamic ileus, in which the bowel wall simply stops moving. This distinction mattered enormously for practice. A mechanical obstruction demanded surgical relief, while a paralyzed bowel called for decompression, supportive care, and patience. The word ileus, once a single ominous label, had split into two conceptually different diseases, and the tension between those meanings would soon shape how one of pediatrics’ signature conditions was first recognized.

It was against this backdrop that the earliest reports of meconium ileus appeared. In 1905, Karl Landsteiner, the Viennese pathologist better known for his discovery of the ABO blood groups, published a description of intestinal obstruction caused by inspissated, or thickened and dried, meconium, which he linked to pancreatic disease. Writing in German, Landsteiner described a bowel blocked not by a band, a volvulus, or an atresia, but by abnormally dense fetal intestinal contents. His observation connected two organ systems, gut and pancreas, in a way that would prove prophetic, though the full significance of that connection took decades to appreciate.

The term meconium ileus itself emerged in the clinical literature shortly afterward. In 1919, Bullowa and Brennan reported a case of intrauterine intestinal obstruction from inspissated and impacted meconium in the Journal of the American Medical Association, framing the problem as a mechanical obstruction present before birth. Here the older, mechanical sense of ileus was doing quiet work: the authors were not describing a paralyzed bowel but a bowel physically plugged by tenacious meconium. The phrase captured a paradox that would puzzle clinicians for years, namely that a newborn could be born already obstructed by a substance that should have passed harmlessly in the first days of life.

Through the 1920s and 1930s, case reports accumulated. In 1936, Dodd published a case report in the Journal of Pediatrics of intestinal obstruction due to meconium ileus in a newborn infant, and the same year Eliason and Johnson addressed the diagnostic features of ileus in the journal Radiology, reflecting the growing role of abdominal radiography in distinguishing patterns of bowel obstruction. Radiographs allowed clinicians to see dilated loops of bowel and, in some cases, a characteristic granular or ground-glass appearance where thick meconium mixed with air. Imaging gave the condition a visible signature and helped separate it from other causes of neonatal obstruction such as atresia, stenosis, and volvulus.

The decisive conceptual breakthrough came in 1936 and 1938. In 1936, Fanconi, Uehlinger, and Knauer published their description of the celiac syndrome associated with congenital cystic fibromatosis of the pancreas and bronchiectasis, drawing together the intestinal, pancreatic, and pulmonary features that had previously been reported in isolation. Two years later, Dorothy Andersen, in a landmark clinical and pathological study in the American Journal of Diseases of Children, defined cystic fibrosis of the pancreas as a distinct disease and established its relationship to the celiac-like syndrome of infants. Within this new framework, meconium ileus found its place: it was not a random mechanical accident of fetal life but the earliest clinical manifestation of a hereditary disorder that thickened secretions throughout the body.

Once cystic fibrosis was defined, the meaning of meconium ileus settled into its modern form. The condition is now understood as neonatal intestinal obstruction caused by abnormally viscous meconium, the product of deficient pancreatic enzyme secretion and altered mucus, which accumulates in the terminal ileum and cecum and produces a mechanical blockage. In the vocabulary of the early twentieth century, that made meconium ileus a true mechanical ileus, in the tradition of Steele’s 1901 discussion of ileus due to mechanical obstruction to the fecal current, rather than a paralytic ileus of the kind Wathen described in his 1909 JAMA paper on postoperative ileus. The newborn bowel in meconium ileus is not lazy; it is blocked, and it strains against a plug of material too thick to pass.

Zarka’s commentary highlights how this history illustrates a broader point about medical language. The word ileus arrived in the meconium literature carrying its ancient sense of severe intestinal suffering, was refined by surgeons into a distinction between mechanical and adynamic obstruction, and then, in the phrase meconium ileus, preserved a specific mechanical meaning that clinical experience gradually clarified. What began as a descriptive label for a mysterious neonatal catastrophe became, through the accumulation of cases, the application of new imaging techniques, and the recognition of cystic fibrosis, a precise diagnostic entity with a defined pathophysiology. The forgotten layers of the term’s meaning were not lost so much as overwritten, and revisiting them reveals how much of modern terminology encodes older debates.

The story also underscores the value of clinical observation in advance of molecular understanding. Landsteiner linked inspissated meconium to pancreatic disease decades before the genetic basis of cystic fibrosis was known. Bullowa and Brennan recognized intrauterine obstruction before any treatment was possible. Andersen’s synthesis transformed scattered reports into a coherent disease concept. Each step depended on clinicians taking seriously what they saw at the bedside and in the pathology laboratory, and on a vocabulary flexible enough, despite its tangled history, to carry those observations forward. In the case of meconium ileus, the curious history of a single word helped keep a forgotten meaning alive long enough for medicine to give it a name, a mechanism, and eventually a place within one of the most common hereditary diseases of childhood.

Subject of Research: The historical evolution of the term ileus and its role in the recognition of meconium ileus as an early manifestation of cystic fibrosis

Article Title: The curious history of meconium ileus: how clinical experience revived a forgotten meaning

Article References: Zarka, A. (2026). The curious history of meconium ileus: how clinical experience revived a forgotten meaning. Pediatric Radiology. https://doi.org/10.1007/s00247-026-06777-x

Image Credits: AI Generated

DOI: 10.1007/s00247-026-06777-x

Keywords: meconium ileus, ileus, cystic fibrosis, history of medicine, Karl Landsteiner, Dorothy Andersen, pediatric radiology, intestinal obstruction, neonatology, medical terminology, pancreatic disease, clinical history

The research team, led by Siobhán McClean of University College Dublin with collaborators including Joanna Drabinska, Lucia O’Connor and Caoilin McClean, took advantage of a uniquely valuable resource: an international reference panel of 41 fully sequenced P. aeruginosa strains assembled by De Soyza and colleagues. Within that panel sit three independent series of sequential isolates, each recovered from a different person with cystic fibrosis in a geographically distinct region, and each spanning roughly seven years of infection. The German series comprises AA2, AA43 and AA44, with the latter two isolated 7.5 years after the first and shortly before the patient’s death. The Seattle series from a pediatric patient includes AMT 0060-3, recovered when the child was 7.7 years old, and two later strains isolated 7.9 years afterward. A third series, AMT0023-30 and AMT0023-34, was isolated eight years apart from a patient who was only six months old at the first sampling; the later strain carried 68 unique mutations relative to the earlier one.

Previous phenotypic work on these strains had already established a consistent pattern: reduced virulence in the Galleria mellonella acute infection model was the only trait altered in every late isolate, while pyocyanin production, the blue-green pigment that contributes to tissue damage, fell in four of the five late strains. Motility traits such as swarming and swimming also declined in most late isolates, with some functions lost entirely. What remained unknown was whether these convergent phenotypes reflected convergent molecular changes. To find out, the researchers performed label-free quantitative proteomics on all eight strains, using a Bruker TimsTOF Pro mass spectrometer coupled to an Evosep One chromatography system with PASEF acquisition, and analyzed the data in MaxQuant against the PAO1 reference proteome with a 1 percent false discovery rate.

The scale of change within each series was striking. In the AMT0060 series, 138 proteins changed abundance by at least 1.5-fold in one late strain and 166 in the other, with 57 changes shared between the two. In the AA2 series, 78 proteins changed in AA43 and 267 in AA44, though only 30 overlapped between the two late strains. The AMT0023 pair showed 182 altered proteins. Given the enormous diversity of P. aeruginosa, the team specifically searched for proteins altered in two or more independent series, reasoning that such changes would represent conserved adaptation pathways rather than patient-specific quirks.

The result was remarkable. Only 16 proteins in total were altered across all three series, and 11 of them showed a consistent direction of change: increased abundance in the late strains of every series. In nearly every case, these proteins were undetectable in the early isolates, meaning the underlying genes had been switched on during years of colonization. The probability that the same three proteins, PA2572, PA3819 and PA5028, would show increased abundance in all five late strains from three independent early ancestors by chance alone was calculated at 5.06 × 10⁻⁵³, which the authors describe as very strong evidence of positive selection. Even for the eight proteins that appeared in only one late isolate per patient, the probability of such a pattern arising randomly in a genome of roughly 5,570 open reading frames was 1.6 × 10⁻¹⁹.

The identities of these 11 proteins tell a coherent evolutionary story. PA3819 is an outer membrane lipoprotein with a glycine zipper domain, encoded within the AlgU regulon that governs alginate production and membrane stress responses, and previously linked to Toll-like receptor signaling in mucoid strains. PA2572 is an HD-GYP domain two-component response regulator sitting beside a chemotaxis transducer gene; it binds the sensor PA2573, influences ExoS and pyocyanin production, dampens swarming motility, and does not hydrolyze c-di-GMP unlike its two paralogs. PA3702, better known as WspR, is the diguanylate cyclase response regulator of the Wsp surface-sensing system, which responds to cell envelope stress, suppresses flagellar motility and promotes biofilm formation, consistent with the loss of motility widely reported for chronic isolates. PA5028 and PA1462 are cytoplasmic membrane proteins of the ParAB family, partners of the DNA-binding partitioning protein ParB, whose systems regulate cell division and act as global regulators of multiple proteins. CifR, a TetR-family epoxide-responsive repressor controlling the CFTR inhibitory factor Cif, rose 10- to 11-fold in one late isolate of each series, matching earlier observations that CF isolates maintain CifR expression over time. The set is rounded out by PA2551, a probable LysR-family transcriptional regulator that may counteract stress-induced growth slowdown; PA2679, a methyltransferase whose expression rises under hypoxia; PA2883, a membrane protein co-expressed with the c-di-GMP-binding protein MapZ and strongly induced by airway epithelia; PA3084, a hypothetical protein identified as conditionally essential for cardiomyocyte infection; and PA3271, a two-component sensor kinase whose disruption alters virulence genes including pyochelin synthesis, elastase and flagellar proteins.

Notably absent from this list are antibiotic resistance mechanisms, even though several resistance-associated proteins, such as the MexA efflux component, rose dramatically in some late strains. The authors suggest that differing antibiotic regimens among the three patients may explain the lack of a conserved resistance signature. Convergence was also evident at the pathway level rather than the individual protein level: virulence-associated secretion systems and secreted factors declined across multiple strains, and phenazine biosynthesis enzymes such as PhzB, PhzF and PhzG dropped in the AA2 and AMT0023 series but not in AMT0060, indicating that reduced pyocyanin production can arise through multiple regulatory routes, including quorum sensing and quinolone signaling, where LasR and PQS-associated proteins were also reduced.

To test whether the upregulated proteins actually confer a functional advantage, the team compared gene-deletion mutants of PA2572 and PA3819 with the wild-type MPAO1 strain under stresses that mimic the cystic fibrosis lung. Under normal conditions the mutants grew identically to the wild type, with comparable growth kinetics and stationary-phase densities. But the ΔPA3819 mutant showed clearly impaired survival under oxidative stress from 1 mM hydrogen peroxide, and both mutants fared worse under osmotic stress from 0.5 M sodium chloride and elevated temperature of 45°C. Antibiotic susceptibility testing added a further twist: loss of PA2572 increased susceptibility to imipenem, aztreonam and norfloxacin, while loss of PA3819 increased susceptibility to aztreonam alone. Together, these results suggest that the elevated abundance of these proteins in late isolates directly supports bacterial fitness under chronic-infection conditions and may contribute to the enhanced antibiotic resistance that emerges over years of treatment.

Intriguingly, quantitative PCR showed that the increased protein abundance was not mirrored at the transcript level. Expression of PA3819 was actually repressed 3.5-fold in two late strains, and PA2572 was repressed 5-fold in AA44, pointing to translational or post-translational control. Searching the amino acid sequences of the three consistently upregulated proteins revealed multiple predicted phosphorylation, glycosylation and N-myristoylation sites associated with protein stability, and a shared conserved motif resembling tyrosine phosphorylation sites found in bacterial effectors such as Tir of enteropathogenic Escherichia coli and Tarp of Chlamydia trachomatis. Tyrosine phosphorylation is known to regulate bacterial virulence traits, and the authors propose that such modifications may stabilize these proteins during chronic infection. Because earlier comparative studies of sequential isolates relied on less sensitive methods such as two-dimensional electrophoresis, none of these 11 proteins had previously been flagged as consistently increased, underscoring the power of modern high-throughput proteomics. Each of the 11 proteins, the authors conclude, represents a potential target for adjuvant therapies designed to disable the adaptation process itself and prevent acute infection from hardening into lifelong chronic colonization.

Subject of Research: Proteomic analysis of sequential Pseudomonas aeruginosa strains from cystic fibrosis patients to identify proteins under positive selection during chronic infection

Article Title: Proteomic Analysis of Three Independent Series of Sequential Cystic Fibrosis Strains in an International Pseudomonas aeruginosa Reference Panel Indicates Positive Selection in Late Infection Strains

Article References: Drabinska, J., O'Connor, L., McClean, C., & McClean, S. (2026). Proteomic Analysis of Three Independent Series of Sequential Cystic Fibrosis Strains in an International Pseudomonas aeruginosa Reference Panel Indicates Positive Selection in Late Infection Strains. MicrobiologyOpen, 15(5), Article e70417. https://doi.org/10.1002/mbo3.70417

Image Credits: AI Generated

DOI: 10.1002/mbo3.70417

Keywords: Pseudomonas aeruginosa, cystic fibrosis, proteomics, chronic infection, positive selection, bacterial adaptation, virulence, two-component regulators, antibiotic resistance, WspR, hypoxia response, host adaptation