Biology subjects

van der Poll, T.

Publications and source records attributed to van der Poll, T..

8 recordsLinked to original sources

bioRxiv2025

Flagellin-mediated TLR5 activation enhances innate immune responses in healthy and diseased human airway epithelium

Bacterial pneumonia poses a significant challenge to public health, often leading to antibiotic treatment failure. Enhancing innate immunity represents a promising adjunctive strategy to conventional antibiotic therapy. Bacterial flagellin, a Toll-like receptor 5 (TLR5) agonist, has been shown to stimulate innate immune defenses when delivered via the respiratory route, demonstrating efficacy in both preventing and treating bacterial pneumonia in murine models. This protective effect is primarily mediated through TLR5-driven activation of airway epithelial cells. This study aimed to characterize the immunomodulatory effects of flagellin on human primary respiratory epithelium. Using the MucilAir air-liquid interface model and RNA sequencing, we demonstrated that apical administration of flagellin induced robust immune responses in airway epithelium derived from healthy individuals, as well as patients with chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF). TLR5-mediated epithelial signaling triggered key immune-related pathways, including cytokine production, leukocyte chemotaxis, neutrophil recruitment, and antimicrobial defense, with strong commonalities across healthy and diseased airway epithelia. Furthermore, we demonstrated that flagellin effectively activated epithelial immune responses even in the presence of the bacteria Pseudomonas aeruginosa or Streptococcus pneumoniae. However, epithelial activation alone was insufficient to directly limit bacterial colonization or replication, highlighting the potential role of epithelial-immune cell interactions in achieving effective bacterial clearance. These findings support TLR5 activation as a promising therapeutic strategy to enhance host defense mechanisms and improve treatment outcomes for bacterial pneumonia in both healthy individuals and patients with COPD or CF.

immunology↗

bioRxiv2025

A bioenergetic basis for multiorgan dysfunction in sepsis

Sepsis is a life-threatening multiorgan dysfunction that develops from a maladaptive host response to infection1. With an estimated 49 million cases per year and [~]11 million related deaths2, sepsis is a global WHO health priority3. Failure to overcome sepsis morbidity and lethality4,5 calls for alternative therapeutic approaches6-8. Here we report that adipocyte lipolysis is vital to prevent the pathogenesis of sepsis in mice. This protective response is evolutionary conserved, producing a plasma lipidomic profile9,10 that reflects on the severity of clinical sepsis. Mechanistically, adipocyte lipolysis fuels energy metabolism to sustain adaptive thermoregulation to infection, via insulin production and insulin receptor (INSR) signaling in adipocytes. This metabolic-based defense strategy does not impact on bacterial burden, establishing disease tolerance to infection11-14. In conclusion, adipocyte lipolysis induces insulin to rewire energy metabolism and support organ function in response to infection.

pathology↗

bioRxiv2024

International multi-cohort analysis identifies novel framework for quantifying immune dysregulation in critical illness: results of the SUBSPACE consortium

Progress in the management of critical care syndromes such as sepsis, Acute Respiratory Distress Syndrome (ARDS), and trauma has slowed over the last two decades, limited by the inherent heterogeneity within syndromic illnesses. Numerous immune endotypes have been proposed in sepsis and critical care, however the overlap of the endotypes is unclear, limiting clinical translation. The SUBSPACE consortium is an international consortium that aims to advance precision medicine through the sharing of transcriptomic data. By evaluating the overlap of existing immune endotypes in sepsis across over 6,000 samples, we developed cell-type specific signatures to quantify dysregulation in these immune compartments. Myeloid and lymphoid dysregulation were associated with disease severity and mortality across all cohorts. This dysregulation was not only observed in sepsis but also in ARDS, trauma, and burn patients, indicating a conserved mechanism across various critical illness syndromes. Moreover, analysis of randomized controlled trial data revealed that myeloid and lymphoid dysregulation is linked to differential mortality in patients treated with anakinra or corticosteroids, underscoring its prognostic and therapeutic significance. In conclusion, this novel immunology-based framework for quantifying cellular compartment dysregulation offers a valuable tool for prognosis and therapeutic decision-making in critical illness.

immunology↗

bioRxiv2022

Single-cell transcriptomics reveals subset-specific metabolic profiles underpinning the bronchial epithelial response to flagellin

Respiratory epithelial cells line the airways and represent the first line of defense against respiratory pathogens. The cellular heterogeneity of the airway wall has only recently been recognized by single-cell analyses. Here, we leveraged single-cell RNA sequencing of primary human bronchial epithelial cells growing in air-liquid interface to determine cell-specific changes evoked by flagellin, a protein driving the motility of many mucosal pathogens. We detected seven cell clusters in the human epithelium, including ciliated cells, ionocytes and several states of basal and secretory cells, of which only inflammatory basal cells and inflammatory secretory cells showed a proportional increase in response to flagellin. Only inflammatory secretory cells showed evidence of metabolic reprogramming toward aerobic glycolysis, and inhibition of the mTOR pathway specifically reduced this subset, prevented this metabolic shift, and reduced inflammatory gene transcription in these cells. This study expands our knowledge of the airways immune response to flagellated pathogens to single cell resolution and defines a novel target to modulate mucosal immunity during bacterial infections.

immunology↗

bioRxiv2020

Distinct cellular immune profiles in the airways and blood of critically ill patients with COVID 19

Our understanding of the coronavirus disease-19 (COVID-19) immune response is almost exclusively derived from studies that examined blood. To gain insight in the pulmonary immune response we analysed BALF samples and paired blood samples from 17 severe COVID-19 patients. Macrophages and T cells were the most abundant cells in BALF. In the lungs, both CD4 and CD8 T cells were predominantly effector memory cells and expressed higher levels of the exhaustion marker PD-1 than in peripheral blood. Prolonged ICU stay associated with a reduced proportion of activated T cells in peripheral blood and even more so in BALF. T cell activation in blood, but not in BALF, was higher in fatal COVID-19 cases. Increased levels of inflammatory mediators were more pronounced in BALF than in plasma. In conclusion, the bronchoalveolar immune response in COVID-19 has a unique local profile that strongly differs from the immune profile in peripheral blood. SummaryThe bronchoalveolar immune response in severe COVID-19 strongly differs from the peripheral blood immune profile. Fatal COVID-19 associated with T cell activation blood, but not in BALF.

immunology↗

bioRxiv2020

Intestinal transkingdom analysis on the impact of antibiotic perturbation in health and critical illness

Bacterial microbiota play a critical role in mediating local and systemic immunity, and shifts in these microbial communities have been linked to impaired outcomes in critical illness. Emerging data indicate that other intestinal organisms, including bacteriophages, viruses of eukaryotes, fungi, and protozoa, are closely interlinked with the bacterial microbiota and their host, yet their collective role during antibiotic perturbation and critical illness remains to be elucidated. Here, multi-omics factor analysis (MOFA), a novel computational strategy to systematically integrate viral, fungal and bacterial sequence data, we describe the functional impact of exposure to broad-spectrum antibiotics in healthy volunteers and critically ill patients. We observe that a loss of the anaerobic intestinal environment is directly correlated with an overgrowth of aerobic pathobionts and their corresponding bacteriophages, as well as an absolute enrichment of opportunistic yeasts capable of causing invasive disease. These findings further illustrate the complexity of transkingdom interactions within the intestinal environment, and show that modulation of the bacterial component of the microbiome has implications extending beyond this kingdom alone.

microbiology↗

bioRxiv2017

Myocardial injury in critically ill patients with community-acquired pneumonia

BackgroundMyocardial injury, as reflected by elevated cardiac troponin levels in plasma, is common in patients with community-acquired pneumonia (CAP), but its temporal dynamics and etiology remain unknown. Our aim was to determine the incidence of troponin release in patients with CAP and identify risk factors which may point to underlying etiologic mechanisms.\n\nMethodsWe included consecutive patients admitted with severe CAP to two intensive care units in the Netherlands between 2011 and 2015. High-sensitivity cardiac troponin I was measured daily during the first week. We used multivariable linear regression to identify variables associated with troponin release on admission, and mixed-effects regression to model the daily rise and fall of troponin levels over time.\n\nResultsAmong 200 eligible patients, 179 were included, yielding 792 observation days. A total of 152 (85%) patients developed raised troponin levels >26 ng/L. Baseline factors independently associated with troponin release included coronary artery disease (160% increase, 95% CI 7-529), smoking (304% increase, 95% CI 59-924), and higher APACHE IV score (2% increase, 95% CI 0.7-3.3), whereas Staphylococcus aureus as a causative pathogen was protective (67% reduction, 95% CI 9-88). Time-dependent risk factors independently associated with daily increase in troponin concentrations included reduced platelet count (1.7% increase, 95% CI 0.1-3.4), tachycardia (1.6% increase, 95% CI 0.3-3), hypotension (5.1% increase, 95% CI 1-9.4) and dobutamine use (38.4% increase 95% CI 8.8-76).\n\nConclusionsCardiac injury develops in a majority of patients with severe CAP. Myocardial oxygen supply-demand mismatch and activated coagulation are potential causes of this injury.

epidemiology↗

bioRxiv2017

Validation Of A Novel Molecular Host Response Assay To Diagnose Infection In Hospitalized Patients Admitted To The ICU With Acute Respiratory Failure

PurposeThe discrimination between infectious and non-infectious causes of acute respiratory failure (ARF) in hospitalized patients admitted to the intensive care unit (ICU) is difficult. Using a novel diagnostic test measuring the expression of four RNA biomarkers in blood (SeptiCyte LAB) we aimed to distinguish between infection and inflammation in this setting.\n\nMethodsWe enrolled hospitalized patients with ARF requiring prompt intubation in the ICU from 2011 to 2013. We excluded patients having an established infection diagnosis or an evidently non-infectious reason for intubation. Blood samples were collected upon ICU admission. Test results were categorized into four probability bands (with higher bands indicating a higher probability of infection) and compared with the plausibility of infection as rated by post-hoc assessment using predefined definitions.\n\nResultsOf 467 included patients, 373 (80%) were treated for a suspected infection at admission. Plausibility of infection was classified as ruled-out, undetermined, or confirmed in 41 (11%), 135 (36%), and 197 (53%) of these, respectively. Overall, the pre-test probability of infection was 42%. Test results correlated with the plausibility of infection (Spearmans rho 0.332; p<0.001). After exclusion of undetermined cases, positive predictive values were 29%, 54%, and 76% for probability bands 2, 3, and 4, respectively, whereas the negative predictive value for band 1 was 76%. However, SeptiCyte LAB did not outperform CRP when comparing diagnostic discrimination (AUC 0.731; 95%CI 0.677-0.786 vs. 0.727; 95%CI 0.666-0.788).\n\nConclusionIn a setting of hospitalized patients admitted to the ICU with ARF, the diagnostic value of SeptiCyte LAB seems limited.

epidemiology↗