Institute of Medical Microbiology and Hygiene

Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease characterized by progressive biliary destruction and cholestasis. Current therapies, including ursodeoxycholic acid (UDCA), exhibit limited efficacy in advanced disease. In this study, we investigate the therapeutic potential of microbial intervention using Lactobacillus rhamnosus (Lbr) in the Mcpip1fl/flAlbCre knockout mouse model of PBC, which we described previously. Knockout mice develop human PBC-like features such as bile acid dysregulation, autoantibodies, cholangiocyte hyperplasia and fibrosis. Six-week-old Mcpip1fl/fl (wild-type) and Mcpip1fl/flAlbCre (knockout) mice were treated with Lactobacillus rhamnosus supplementation, UDCA (15mg/kg/day), UDCA + Lbr, and UDCA + OCA (obeticholic acid, 10mg/kg/day) for six weeks. Treatment response was characterized by liver and gut pathology, serum biomarkers, transcriptomic profiles, and microbiome composition. Treatment of Mcpip1fl/flAlbCre animals with Lbr decreased serum bile acids and reduced pathological cholangiocyte dysplasia in the liver, decreased leukocyte infiltration and fibrosis. RNAseq of liver tissue revealed enrichment of humoral immune responses and T cell activation pathways in knockouts, all of which were significantly attenuated by Lbr monotherapy. Gut pathology marked by increased intraepithelial lymphocyte infiltration and mucosal hypertrophy, was also normalized upon Lbr administration. Finally, probiotic treatment modulated the microbiome by increasing the Firmicutes/Bacteroidetes ratio and enriching butyrate-producing Lachnospiraceae. Administration of UDCA and UDCA+OCA had less pronounced effects: only decreased serum bile acids was detected in both groups. Probiotic intervention with Lbr represents a feasible strategy to attenuate fibrotic progression in a mouse model of autoimmune cholestatic disease by modulation of the gut-microbiome-immune crosstalk.

The Bacillus Calmette-Guérin (BCG) vaccine protects infants from severe tuberculosis by eliciting cellular immune responses, particularly through the activation of CD8+ cytotoxic T lymphocytes. Given that hypoxia is a defining feature of the pulmonary microenvironment during Mycobacterium tuberculosis infection, especially within granulomatous lesions, we investigated how limited oxygen availability influences the expansion and effector functions of BCG-induced cytotoxic T cells. Mycobacteria-specific short-term T-cell lines were generated and restimulated with BCG-infected macrophages under normoxic and hypoxic conditions. To analyze the immune response, Boolean gating was applied to flow cytometry data to compare the frequencies of cytotoxic T-cell subsets within BCG-responsive CD8+ T-cell population. Under normoxia, BCG-responsive CD8+ T cells exhibited elevated expression of perforin, granulysin, and granzyme B, with a significant enrichment of polycytotoxic cells co-expressing all three molecules. Hypoxia differentially modulated these markers: perforin expression remained unchanged, granulysin was substantially increased, whereas granzyme B declined, resulting in a net reduction of polycytotoxic T cells. These findings demonstrate that oxygen availability shapes the functional profile of vaccine-induced cytotoxic T cells. Considering the hypoxic nature of inflamed and infected lung tissue, our results highlight the importance of evaluating vaccine efficacy in physiologically relevant microenvironments and may inform strategies to enhance polycytotoxic T-cell responses for improved tuberculosis protection.

To investigate the microbiological etiology of endogenous and exogenous postprocedural infectious endophthalmitis in patients referred to two tertiary eye care centers in the German federal state of Saarland over a five-year period (2019-2023). We retrospectively analyzed all cases of endophthalmitis treated at two ophthalmological centers in southwest Germany between January 1, 2019, and December 31, 2023. Included were only those cases for which vitreous aspirate specimens were subjected to microbiological analysis. Cases of exogenous endophthalmitis secondary to other ocular or periocular infections (e.g., microbial keratitis) or trauma were excluded. Microbiological pathogen identification was performed using Gram stain microscopy, conventional bacterial and fungal cultures, as well as broad-range bacterial and fungal polymerase chain reaction (PCR), followed by sequencing in PCR-positive samples. A total of 126 endophthalmitis vitreous aspirate samples from 126 patients with a mean age of 73.3 ± 11.4years were included. The majority of endophthalmitis cases occurred after intravitreal injection (55.6%), followed by previous cataract surgery (23.8%), pars plana vitrectomy (5.6%), and glaucoma surgery (4.8%). Only 7.9% of all cases were endogenous. Overall, pathogens were identified in 58.7% (n = 74) of all cases, with culture yielding a higher detection rate compared to PCR (53.2% versus 43.5%). Staphylococcus epidermidis was most commonly detected (n = 43; 58.1%), followed by Staphylococcus aureus (n = 7; 9.5%) and Enterococcus faecalis (n = 5; 6.8%). Postinjection and postcataract endophthalmitis tended to be associated with positive bacterial culture results, whereas endogenous endophthalmitis was more frequently associated with negative bacterial culture results (p = 0.06). Fungal endophthalmitis was detected in three samples, of which the endogenous cases were caused by Candida albicans (n = 2). Bacterial multidrug resistance was rare, with only a single detected methicillin-resistant S. aureus strain. All Gram-positive bacteria were susceptible to vancomycin. Our results confirm S. epidermidis to be the most common endophthalmitis-causing pathogen. No single microbiological diagnostic technique would have identified all cases of infection, thus calling for combined approaches that include culture and molecular testing.

Background Despite growing scientific evidence and health guidelines, the global health paradox persists, with rising lifestyle-related diseases and escalating healthcare costs exposing the inadequacy of current efforts. Objective Three multidisciplinary congresses were held to generate evidence-based conclusions aimed at addressing the global health paradox. Methods A total of 58 experts from 62 entities participated in the international research and knowledge-exchange panels. Experts reviewed the latest findings to develop practical strategies and identify key research and policy priorities, focusing on the Healthy Eating & Active Living (HEAL) approach. Results, conclusion, and relevance The expert consortium endorsed a 33 evidence-based consensual-statement policy roadmap for addressing global health challenges, emphasizing that the HEAL approach can significantly contribute to the “Prevention First” appeal and broad ethical, social, ecological, and economic advantages, and ultimately supporting policy change.

Abstract All animals age. However, aging is a heterogeneous process and individual organisms age differently. Moreover, within the same organism, cells or organs do not age at the same time or speed. For instance, although neurodegeneration is a key trait of aging, neurological symptoms normally manifest long after multiple indicators of aging in peripheral tissues. The genetic determinants of aging remain poorly understood. Mutations in leucine-rich repeat kinase 2 (LRRK2) are major genetic risk factors for Parkinson’s disease (PD). By analyzing PD patients and mice with LRRK2 gain of function mutation (LRRK2 GoF ), we demonstrate that PD is an accelerated aging disease characterized by systemic low-grade STING-dependent inflammation (inflammaging) that first manifests in the periphery then disrupts the blood brain barrier and progresses to the brain resulting in neurodegeneration. Mechanistically, we demonstrate that a primary consequence of aging or Lrrk2 GoF is endolysosomal decline. This results in the cytosolic build-up of extraneous self-DNA and subsequent shedding of DNA-containing extracellular vesicles thereby triggering the cGAS- STING pathway cell-intrinsically and intercellularly in distant host cells. This study unveils the cGAS-STING pathway and LRRK2 GoF as key determinants and potential targets for preventive or therapeutic strategies against accelerated aging, inflammaging and neurodegeneration.

Background/Objectives: Nosocomial outbreaks of viral respiratory infections strain healthcare systems and endanger patients and healthcare workers (HCWs). We describe two large nosocomial outbreaks with the SARS-CoV-2 Alpha variant, during its initial emergence in Germany, to assess transmission dynamics, effectiveness of control measures, and challenges in managing highly transmissible respiratory viruses. Methods: Confirmed cases were inpatients, HCWs, or their contacts testing SARS-CoV-2-positive since 1 January 2021 (Hospital A [HA])) or 21 January 2021 (Hospital B [HB])) with N501Y and delH69/V70 spike gene mutations. We conducted case interviews, reviewed medical records and shift schedules, and performed sequencing, genome reconstruction, and phylogenetic analysis. We describe cases, transmission chains, and control measures. Results: HA reported 18 patient cases, 20 HCW cases, and 33 community cases (N = 71). HB reported 48 patient cases, 43 HCW cases (13 in a COVID-19 ward), and 27 community cases (N = 118). In-hospital transmission occurred patient-to-patient, HCW-to-patient, patient-to-HCW, and HCW-to-HCW. HA halted admissions immediately after the initial cases; HB implemented measures gradually. Regular testing detected pre-symptomatic (HA = 6; HB = 18) and asymptomatic cases (HA = 3; HB = 13). Testing of agency staff was incomplete. The suspected primary case was an HCW in HA and a patient in HB who required resuscitation shortly after admission. Conclusions: Early COVID-19 outbreaks offer valuable lessons for managing emerging nosocomial outbreaks of highly transmissible respiratory viruses. Our findings provide empirical evidence for effective interventions, including rapid response, testing, HCW protection, and rigorous contact tracing in high-risk emergency situations. Managing agency staff remains a major challenge.

[This corrects the article DOI: 10.3389/fpubh.2025.1654772.].

Abstract Hepatitis E virus (HEV) is considered a predominantly foodborne pathogen in developed settings. During COVID-19 lockdown periods, however, HEV concentrations in wastewater at a treatment plant in Munich, Germany decreased, suggesting that pandemic-related behaviour changes inadvertently influenced transmission. In contrast, reported cases and wastewater data from a smaller catchment showed no comparable decline. To assess whether the observed reduction is compatible with a near-exclusively foodborne infection and to reconcile the contrasting signals across surveillance modalities, we developed a stochastic, individual-level model of HEV transmission, shedding, and ascertainment in Munich. Using Approximate Bayesian Computation, we calibrated this model to wastewater and case data from 2020–2023, first separately and then jointly. Posterior parameter estimates indicated a substantial decline in transmission during lockdowns to about 35–40% of the non-lockdown level, with the 95% credible interval entirely below 1 (no change). Joint inference suggested that possible modest lockdown-associated increases in diagnosis probabilities and higher measurement variability in the smaller catchment masked this effect in clinical and small-scale wastewater data, respectively. These findings demonstrate how wastewater-based surveillance, used alongside reported cases, can enable more robust parameter inference for models of under-reported pathogens like HEV, thereby supporting informed public health risk assessments.

The growing resistance of Enterobacterales to last-resort antibiotics such as carbapenems puts a significant burden on healthcare systems, also due to plasmids driving a rapid spread of carbapenem resistance. We here evaluate the use of long-read nanopore sequencing to investigate carbapenem resistance dynamics and the role of plasmid transfers and environmental reservoirs in the hospital setting. Over 13 months, routine clinical diagnostics identified recurring isolates of carbapenem-resistant Citrobacter species carrying Klebsiella pneumoniae carbapenemases (KPCs) and/or OXA-48-like carbapenemases from patient screening and hospital drain samples. While routine diagnostic approaches provided limited insights into the carbapenem resistance dynamics, we show that near-complete de novo assembly of chromosomes and plasmids by long-read nanopore sequencing allowed for high-resolution strain identification, plasmid profiling, and antibiotic resistance gene detection. Notably, genomically nearly indistinguishable Citrobacter freundii of the high-risk sequence type ST91 genomes were recovered from screening samples collected in the same hospital room 1 year apart. We further provide evidence of a KPC-2-encoding IncN plasmid that is likely to have spread across bacterial species and between patient and drain isolates, which emphasizes the role of contaminated drains in the persistence and dissemination of antimicrobial resistance within the hospital environment. Overall, this study demonstrates the value of long-read nanopore sequencing for uncovering the complex dynamics of carbapenem resistance spread and persistence in the hospital setting and its potential implications for infection prevention and control.