Coronavirus disease 2019 (COVID-19), caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), comprises mild courses of disease as well as progression to severe disease, characterised by lung and other organ failure. The immune system is considered to play a crucial role for the pathogenesis of COVID-19, although especially the contribution of innate-like T cells remains poorly understood. Here, we analysed the phenotype and function of mucosal-associated invariant T (MAIT) cells, innate-like T cells with potent antimicrobial effector function, in patients with mild and severe COVID-19 by multicolour flow cytometry. Our data indicate that MAIT cells are highly activated in patients with COVID-19, irrespective of the course of disease, and express high levels of proinflammatory cytokines such as IL-17A and TNFα ex vivo. Of note, expression of the activation marker HLA-DR positively correlated with SAPS II score, a measure of disease severity. Upon MAIT cell-specific in vitro stimulation, MAIT cells however failed to upregulate expression of the cytokines IL-17A and TNFα, as well as cytolytic proteins, that is, granzyme B and perforin. Thus, our data point towards an altered cytokine expression profile alongside an impaired antibacterial and antiviral function of MAIT cells in COVID-19 and thereby contribute to the understanding of COVID-19 immunopathogenesis.

We aimed to analyse whether patients with ischaemic stroke (IS) occurring within eight days after the onset of COVID-19 (IS-COV) are associated with a specific aetiology of IS. We used SUPERGNOVA to identify genome regions that correlate between the IS-COV cohort (73 IS-COV cases vs. 701 population controls) and different aetiological subtypes. Polygenic risk scores (PRSs) for each subtype were generated and tested in the IS-COV cohort using PRSice-2 and PLINK to find genetic associations. Both analyses used the IS-COV cohort and GWAS from MEGASTROKE (67,162 stroke patients vs. 454,450 population controls), GIGASTROKE (110,182 vs. 1,503,898), and the NINDS Stroke Genetics Network (16,851 vs. 32,473). Three genomic regions were associated (p-value < 0.05) with large artery atherosclerosis (LAA) and cardioembolic stroke (CES). We found four loci targeting the genes PITX2 (rs10033464, IS-COV beta = 0.04, p-value = 2.3 × 10⁻², se = 0.02), previously associated with CES, HS6ST1 (rs4662630, IS-COV beta = −0.04, p-value = 1.3 × 10⁻³, se = 0.01), TMEM132E (rs12941838 IS-COV beta = 0.05, p-value = 3.6 × 10⁻⁴, se = 0.01), and RFFL (rs797989 IS-COV beta = 0.03, p-value = 1.0 × 10⁻², se = 0.01). A statistically significant PRS was observed for LAA. Our results suggest that IS-COV cases are genetically similar to LAA and CES subtypes. Larger cohorts are needed to assess if the genetic factors in IS-COV cases are shared with the general population or specific to viral infection.

Purpose: The benefit of antibiotic treatment (ABT) for patients with moderate COVID-19 is unclear and overtreatment poses the risk of adverse effects such as Clostridioides difficile infection and antibiotic resistance. This multi-center study compares health status improvement between patients with and without ABT at hospital admission. Methods: Between March 2020 and May 2023, hospitalized adults with confirmed SARS-CoV-2 infection were recruited from the German National Pandemic Cohort Network (NAPKON), which includes patients from various hospitals across Germany. The study population included patients with moderate or severe COVID-19 at baseline. The primary objective was to compare health improvement or decline after two weeks between patients who received ABT at baseline and those who did not in the moderate COVID-19 population. The statistical analysis adjusted for confounders such as gender, age, vaccination status, clinical condition, and comorbidities. The severe COVID-19 population was investigated as a secondary objective. Results: A total of 1,317 patients (median age 59 years; 38% women) were eligible for analysis, of whom 1,149 had moderate and 168 severe COVID-19 disease. ABT for pneumonia was administered to 467 patients with moderate and 117 with severe COVID-19. ABT at baseline was significantly associated with a higher deterioration rate after two weeks in patients with moderate COVID-19 (ABT: 292 improvement, 61 deterioration; no ABT: 429 improvement, 14 deterioration). A similar result was obtained in the multiple regression analysis where an odds ratio of 5.00 (95% confidence interval: 2.50 – 10.93) for ABT was observed. Conclusion: We found no benefit of antibiotic therapy in patients with moderate COVID-19. Use of ABT was associated with a higher likelihood of clinical deterioration. Graphical

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies with neoadjuvant radio(chemo)therapy failing in approximately 70 % of cases due to high tumor heterogeneity, and intrinsic radioresistance. Patient-derived organoids (PDOs) closely recapitulate appearance, and functionality as the original tissue and have potential to explore novel therapies for personalized radiooncology. In this study, the radioresponse of PDAC PDO lines was determined after irradiation (RT). PDOs were immunohistochemically characterized by γ-H2AX, HIF-1α and Ki-67 staining. RNA sequencing data were analyzed by gene set enrichment analyses to investigate underlying mechanisms of radioresistance. Preclinical findings were correlated with clinical data from the corresponding patients. PDOs showed a significant heterogeneity in response to radiation and were classified into radiosensitive, intermediate, and radioresistant subgroups. A correlation between radiosensitivity and enhanced proliferation and decreased hypoxia was observed. OXPHOS-related gene signatures were significantly overexpressed in the radioresistant phenotype. Translationally, radioresistance in PDOs was associated with significantly poorer survival of patients. Our platform demonstrated heterogeneity in radioresponse reflecting the clinical situation and correlation with clinical outcomes. Immunohistochemical staining and transcriptomic profiling identified molecular signatures, including HIF-1α and OXPHOS-related pathways, associated with radioresistance. Implementing PDO-based radioresponse profiling in clinical workflows may enable patient stratified treatment approaches. Overall, our findings suggest that functionalizing PDOs for radioresponse might extend PDO-informed precision oncology.