Thomas F Meyer

• Max Planck Institute for Infection Biology

Background Parkinsons disease is a complex multifactorial neurodegenerative disorder characterized by pSer129 alpha Synuclein aggregation in Lewy bodies, with phosphorylation at serine 129 being a critical pathological hallmark. However, the exact mechanisms by which environmental triggers lead to this disease phenotype remain poorly understood. In...

The mucus serves as a protective barrier in the gastrointestinal tract against microbial attacks. While its role extends beyond merely being a physical barrier, the extent of its active bactericidal properties remains unclear, and the mechanisms regulating these properties are not yet understood. We propose that inflammation induces epithelial cell...

Introduction Cervical cancer represents one of the main causes of female, cancer-related mortality worldwide. The majority of cancers are caused by human papillomaviruses such as HPV16 and HPV18. As chemotherapeutic resistance to first-line platinum treatment is still a predominant clinical challenge in advanced cervical cancer, novel treatment opt...

Background Gastric intestinal metaplasia (GIM) is an essential precancerous lesion. Although the reversal of GIM is challenging, it potentially brings a state-to-art strategy for gastric cancer therapeutics (GC). The lack of the appropriate in vitro model limits studies of GIM pathogenesis, which is the issue this work aims to address for further s...

The gastroesophageal squamocolumnar junction (GE-SCJ) is a critical tissue interface between the esophagus and stomach, with significant relevance in the pathophysiology of gastrointestinal diseases. Despite this, the molecular mechanisms underlying GE-SCJ development remain unclear. Using single-cell transcriptomics, organoids, and spatial analysi...

Cervical cancer is a leading cause of death among women globally, primarily driven by high-risk papillomaviruses. However, the effectiveness of chemotherapy is limited, underscoring the potential of personalized immunotherapies. Patient-derived organoids, which possess cellular heterogeneity, proper epithelial architecture and functionality, and lo...

Gastric intestinal metaplasia (GIM) constitutes a pre-neoplastic stage in the development of stomach cancer. While strong evidence points to a role of infection with CagA positive Helicobacter pylori in the development of GIM, currently available experimental models have not provided mechanistic clues on this association. Here, we ectopically expre...

Cervical cancer is a leading cause of death among women globally, primarily driven by high-risk papillomaviruses. However, the effectiveness of chemotherapy is limited, underscoring the potential of personalized immunotherapies. Patient-derived organoids, which possess cellular heterogeneity, proper epithelial architecture and functionality, and lo...

Background Epigenetic modifications in mammalian DNA are commonly manifested by DNA methylation. In the stomach, altered DNA methylation patterns have been observed following chronic Helicobacter pylori infections and in gastric cancer. In the context of epigenetic regulation, the regional nature of the stomach has been rarely considered in detail....

Background High-content screening (HCS) experiments generate complex data from multiple object features for each cell within a treated population. Usually, these data are analyzed by using population-averaged values of the features of interest, increasing the amount of false positives and the need for intensive follow-up validation. Therefore, ther...

Crosstalk within the gastric epithelium, which is closely in contact with stromal fibroblasts in the gastric mucosa has a pivotal impact in proliferation, differentiation and transformation of the gastric epithelium. The human pathogen Helicobacter pylori colonises the gastric epithelium and represents a risk factor for gastric pathophysiology. Inf...

The cervix is the gateway to the upper female reproductive tract, connecting the uterus and vagina. It plays crucial roles in fertility and pregnancy maintenance from onset until delivery of the fetus, and prevents pathogen ascension. Compromised functionality of the cervix can lead to disorders, including infertility, chronic infections and cancer...

Background Epigenetic modifications in mammalian DNA are commonly manifested by DNA methylation. In the stomach, altered DNA methylation patterns have been observed following chronic Helicobacter pylori infections and in gastric cancer. In the context of epigenetic regulation, the regional nature of the stomach has been rarely considered in detail....

Helicobacter pylori causes gastric inflammation, gland hyperplasia and is linked to gastric cancer. Here, we studied the interplay between gastric epithelial stem cells and their stromal niche under homeostasis and upon H. pylori infection. We find that gastric epithelial stem cell differentiation is orchestrated by subsets of stromal cells that ei...

Gut colonization by colibactin-producing bacteria is associated with colorectal cancer. A mutational signature of this genotoxin in human cancer indicates causality but only partially accounts for cell transformation. Instead, the failure of adequately resolving DNA damage causes genomic aberrations and chromosomal instability, constituting the mai...

High content screening (HCS) experiments generate complex data from multiple object features for each cell within a treated population. Usually these data are analyzed by using population-averaged values of the features of interest, increasing the amount of false positives and the need for intensive follow-up validation. Therefore, there is a stron...

The gastroesophageal junction (GEJ), where squamous and columnar epithelia meet, is a hotspot for Barretts metaplasia development, dysbiosis and carcinogenesis. However, the mechanisms regulating GEJ homeostasis remain unclear. Here, by employing organoids, bulk and single-cell transcriptomics, single-molecule RNA in situ hybridisations and lineage...

Helicobacter pylori infection constitutes one of the major risk factors for the development of gastric diseases including gastric cancer. The activation of nuclear factor-kappa-light-chain-enhancer of activated B cells (NF-κB) via classical and alternative pathways is a hallmark of H. pylori infection leading to inflammation in gastric epithelial c...

Viruses manipulate cellular metabolism and macromolecule recycling processes like autophagy. Dysregulated metabolism might lead to excessive inflammatory and autoimmune responses as observed in severe and long COVID-19 patients. Here we show that SARS-CoV-2 modulates cellular metabolism and reduces autophagy. Accordingly, compound-driven induction...

Background & Aims The homeostasis of the gastrointestinal epithelium relies on cell regeneration and differentiation into distinct lineages organised inside glands and crypts. Regeneration depends on WNT/β-Catenin pathway activation, but to understand homeostasis and its dysregulation in disease we need to identify the signalling microenvironment g...

Cervical mucosa is continually confronted by coinfections with pathogenic microbes. In addition to human papillomavirus, coinfections with Chlamydia trachomatis have been associated with an increased risk of cervical cancer. However, the dynamics of coinfections, their impact on the epithelia, and their contribution to pathogenesis remain obscure....

Genotoxic colibactin-producing pks + Escherichia coli induce DNA double-strand breaks, mutations, and promote tumor development in mouse models of colorectal cancer (CRC). Colibactin’s distinct mutational signature is reflected in human CRC, suggesting a causal link. Here, we investigate its transformation potential using organoids from primary mur...

The transition zones of the squamous and columnar epithelia constitute hotspots for the emergence of cancer, often preceded by metaplasia, in which one epithelial type is replaced by another. It remains unclear how the epithelial spatial organization is maintained and how the transition zone niche is remodelled during metaplasia. Here we used singl...

Emerging mosquito-borne RNA viruses cause massive health complications worldwide. The Zika virus (ZIKV), in particular, has spread dramatically since 2007 and has provoked epidemics in the Americas and the South Pacific. The lack of antiviral therapy and vaccination has focused research on the investigation of ZIKV–host interactions, in order to un...

Exposure of gastric epithelial cells to the bacterial carcinogen Helicobacter pylori causes DNA double strand breaks. Here, we show that H. pylori-induced DNA damage occurs co-transcriptionally in S-phase cells that activate NF-κB signaling upon innate immune recognition of the lipopolysaccharide biosynthetic intermediate β-ADP-heptose by the ALPK1...

Bacterial infections are increasingly being recognized as risk factors for the development of adenocarcinomas. The strong epidemiological evidence linking Helicobacter pylori infection to stomach cancer has paved the way to the demonstration that bacterial infections cause DNA damage in the host cells, initiating transformation. In this regard, the...

Exceptional genetic diversity and variability are hallmarks of Helicobacter pylori , but the biological role of this plasticity remains incompletely understood. Here, we had the rare opportunity to investigate the molecular evolution during the first weeks of H. pylori infection by comparing the genomes and epigenomes of H. pylori strain BCS 100 us...

Cdc-like kinase 1 (CLK1) is a dual-specificity kinase capable of autophosphorylation on tyrosine residues and Ser/Thr phosphorylation of its substrates. CLK1 belongs to the CLK kinase family that regulates alternative splicing through phosphorylation of serine-arginine rich (SR) proteins. Recent studies have demonstrated that CLK1 has an important...

The mucosal epithelium is a common target of damage by chronic bacterial infections and the accompanying toxins, and most cancers originate from this tissue. We investigated whether colibactin, a potent genotoxin¹ associated with certain strains of Escherichia coli², creates a specific DNA-damage signature in infected human colorectal cells. Notabl...

Human guanylate binding protein 1 (hGBP1) belongs to the dynamin superfamily of GTPases and conveys host defense against intracellular bacteria and parasites. During infection, hGBP1 is recruited to pathogen-containing vacuoles, such as Chlamydia trachomatis inclusions, restricts pathogenic growth, and induces the activation of the inflammasome pat...

High-grade serous ovarian cancer (HGSOC) likely originates from the fallopian tube (FT) epithelium. Here, we established 15 organoid lines from HGSOC primary tumor deposits that closely match the mutational profile and phenotype of the parental tumor. We found that Wnt pathway activation leads to growth arrest of these cancer organoids. Moreover, a...

Background Deregulated c-Abl activity has been intensively studied in a variety of solid tumors and leukemia. The class-I carcinogen Helicobacter pylori (Hp) activates the non-receptor tyrosine kinase c-Abl to phosphorylate the oncoprotein cytotoxin-associated gene A (CagA). The role of c-Abl in CagA-dependent pathways is well established; however,...

Colibactin, a potent genotoxin of Escherichia coli , causes DNA double strand breaks (DSBs) in human cells. We investigated if colibactin creates a particular DNA damage signature in infected cells by identifying DSBs in colon cells after infection with pks + E.coli . Interestingly, genomic contexts of DSBs were enriched for AT-rich penta-/hexameri...

The colonic epithelial turnover is driven by crypt-base stem cells that express the R-spondin receptor Lgr5. Signals that regulate epithelial regeneration upon stem cell injury are largely unknown. Here, we explore the dynamics of Wnt signaling in the colon. We identify two populations of cells with active Wnt signaling: highly proliferative Lgr5+/...

High-grade serous ovarian cancer (HGSOC) likely originates from the fallopian tube (FT) epithelium. Here, we established 15 organoid lines from HGSOC primary tumor deposits that closely match the parental tumor mutational profile and phenotype. We found that Wnt pathway activation leads to growth arrest of these cancer organoids. Moreover, active B...

Subject of the invention is a method for long-term culture of columnar epithelial cells and the application thereof. The cells in culture survive more than 6 months and they can be expanded due to their regenerative capacity. The epithelial cells are seeded on a thin matrix-coated solid semi-permeable filter and cultivated in an air liquid interfac...

Breast cancer is the most common cancer in women worldwide. Despite recent developments in breast cancer detection and treatment, 1.38 million women each year are still affected. Breast cancer heterogeneity at the population and single-cell level, complexity and developing different metastases are setting several challenges to develop efficient bre...

Wnt signalling stimulated by binding of R-spondin (Rspo) to Lgr-family members is crucial for gastrointestinal stem cell renewal. Infection of the stomach with Helicobacter pylori stimulates increased secretion of Rspo by myofibroblasts, leading to an increase in proliferation of Wnt-responsive Axin2⁺Lgr5⁻ stem cells in the isthmus of the gastric g...

The gastric pathogen Helicobacter pylori activates the NF‐κB pathway in human epithelial cells via the recently discovered α‐kinase 1 TRAF‐interacting protein with forkhead‐associated domain (TIFA) axis. We and others showed that this pathway can be triggered by heptose 1,7‐bisphosphate (HBP), an LPS intermediate produced in gram‐negative bacteria...

Influenza A virus carries eight negative single-stranded RNAs and uses spliced mRNAs to increase the number of proteins produced from them. Several genome-wide screens for essential host factors for influenza A virus re-plication revealed a necessity for splicing and splicing-related factors, including Cdc-like kinase 1 (CLK1). This CLK family kina...

The ability of Helicobacter pylori to persist lifelong in the human gastric mucosa is a striking phenomenon. It is even more surprising since infection is typically associated with a vivid inflammatory response. Recent studies revealed the mechanism by which this pathogen inhibits the epithelial responses to IFN-γ and other central inflammatory cyt...

Modulation of Host Cell Metabolism by Chlamydia trachomatis, Page 1 of 2 Abstract The human obligate intracellular pathogen Chlamydia trachomatis is the most frequent cause of sexually transmitted bacterial infection, with over 130 million cases per year ( 1 ). C. trachomatis causes blinding trachoma and pelvic inflammatory disease, the latter be...

The best measure to limit spread of contagious diseases caused by influenza A viruses (IAVs) is annual vaccination. The growing global demand for low-cost vaccines requires the establishment of high-yield production processes. One possible option to address this challenge is the engineering of novel vaccine producer cell lines by manipulating gene...

Uniprot identifier, names and functions of host cell genes used in this study. (DOCX)

Overexpression level of host cell genes in cell lines overexpressing one of the indicated genes as determined by 2−ΔΔCT method. (DOCX)

Overexpression level of host cell genes in cell lines overexpressing multiple genes (MGOs) as determined by 2−ΔΔCT method. (DOCX)

Parameters used for the simulation of intracellular IAV replication. (DOCX)

Comparison of simulations of intracellular influenza A virus replication in MDCK and parental A549 cells. Model fit (blue lines) to experimental data (blue symbols) for A549 and simulations for MDCK cells (brown lines) are shown, respectively. (A, B) Intracellular dynamics of viral RNA for a simulated infection at MOI 50 for vRNA and cRNA (circles,...

Comparison of parameter distributions for different A549 cell lines. Decadic logarithm of parameter values for fitting 3000 resamplings of the available experimental data obtained from SGOs. Shown are median (red solid line), first and third quartile (blue box), maximum values (whiskers) and outliers (red crosses). Blue dashed lines represent the m...

Flow cytometry measurement of eGFP from parental and transduced A549 cell lines during cell culture maintenance. PFA-fixated cells were measured by imaging flow cytometry using the 488 nm laser. The eGFP signal of single cells in focus was evaluated using the mean FI (mean pixel feature) of channel 2 (CH02) and visualized as histograms for parental...

Summary of in silico optimized kinetic parameters and corresponding model response according to the analysis shown in Fig 1. (DOCX)

Primer sets for reverse transcription and real-time RT-qPCR for segment 5 of A/PR/8/34 (H1N1). (DOCX)

Primer sets for PCR of host cell mRNA. (DOCX)

Simulated virus release dynamics of MGO CFNPX and A549 cells. Light blue area shows the mean and standard deviation of released virions from approximately 2 x 104 simulations with randomized parameter sets, for a simulated infection at MOI 1. Infection of parental A549 cells, the transduction control and SGOs were simulated with the optimized param...

Virus release dynamics in response to in silico manipulation of gene expression of host cell factors in MDCK cells. We assume that efficiency of individual steps in the virus life cycle is directly dependent on host cell factors and that their influence is changed upon knockdown or overexpression of the corresponding gene. We simulated manipulation...

Comparison of key kinetic parameters of influenza A virus replication in parental A549 cells and A549 cells overexpressing selected host cell factors (SGOs). (DOCX)

Primer sets for the generation of RNA reference standards for A/PR/8/34 (H1N1) segment 5. (DOCX)

Fold change in final virus yield in response to parameter perturbations. We simulated manipulation of vRNA synthesis (column 1), viral protein synthesis (column 2) and the binding of the matrix protein 1 (M1) to nuclear vRNPs (column 3) by perturbing the corresponding kinetic parameters in the IAV replication model for both A549 cells established i...

Definition of nucleus and whole cell mask for image analysis of vRNP localization in infected A549 cells. The nucleus mask was defined with the help of the “morphology” feature on CH1 (DAPI signal) and the whole cell mask with the “object” feature on CH6 (bright field). (TIF)

Experimental data. Contains measurements on nuclear import of viral genomes, intracellular viral RNA and virus release. (XLSX)

Simulation of viral components in parental A549 cells and an in silico A549 cell line with changed parameters according to findings for the impact of FANCG on viral polymerase activity, proposed by Tafforeau and colleagues [17]. Virus particle release (A) and dynamics of intracellular vRNA (B), cRNA (C) and mRNA (D) if overexpression of FANCG cause...

Simulation of viral components in parental A549 cells and an in silico A549 cell line with changed parameters according to findings for the impact of FANCG on viral polymerase activity, proposed by Tafforeau and colleagues [17]. Virus particle release (A) and dynamics of intracellular vRNA (B), cRNA (C) and mRNA (D) if overexpression of FANCG cause...

List of the ODE model equations used in the present study to simulate IAV replication in a single cell. (DOCX)

Simulation of viral components in parental A549 cells and an in silico A549 cell line with changed parameters according to findings for the impact of FANCG on viral polymerase activity, proposed by Tafforeau and colleagues [17]. Virus particle release (A) and dynamics of intracellular vRNA (B), cRNA (C) and mRNA (D) if overexpression of FANCG cause...

Influenza viruses (IVs) tend to rapidly develop resistance to virus-directed vaccines and common antivirals targeting pathogen determinants, but novel host-directed approaches might preclude resistance development. To identify the most promising cellular targets for a host-directed approach against influenza, we performed a comparative small interf...

Chronic infections of the fallopian tubes with Chlamydia trachomatis (Ctr) cause scarring and can lead to infertility. Here we use human fallopian tube organoids and genital Ctr serovars D, K and E for long-term in vitro analysis. The epithelial monolayer responds with active expulsion of the bacteria into the lumen and with compensatory cellular p...

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The Cpx-envelope stress system regulates the expression of virulence factors in many Gram-negative pathogens. In Salmonella enterica serovar Typhimurium deletion of the sensor kinase CpxA but not of the response regulator CpxR results in the down regulation of the key regulator for invasion, HilA encoded by the Salmonella pathogenicity island 1 (SP...

Chlamydia trachomatis (Ctr) causes a range of infectious diseases and is epidemiologically associated with cervical and ovarian cancers. To obtain a panoramic view of Ctr-induced signaling, we performed global phosphoproteomic and transcriptomic analyses. We identified numerous Ctr phosphoproteins and Ctr-regulated host phosphoproteins. Bioinformat...

Cervical and ovarian cancers exhibit characteristic mutational signatures that are reminiscent of mutational processes, including defective homologous recombination (HR) repair. How these mutational processes are initiated during carcinogenesis is largely unclear. Chlamydia trachomatis infections are epidemiologically associated with cervical and o...

The transition zones (TZ) between squamous and columnar epithelium constitute hotspots for the emergence of cancers. Carcinogenesis at these sites is often preceded by the development of metaplasia, where one epithelial type invades the neighboring one. It remains unclear how these niches are restrained at the boundary between the two epithelial ty...

The human gastric pathogen Helicobacter pylori occurs in two basic variants, either exhibiting a functional cagPAI‐encoded type‐4‐secretion‐system (T4SS) or not. Only a few cagPAI positive strains have been successfully adapted for long‐term infection of mice, including the pre‐mouse Sydney strain 1 (PMSS1). Here we confirm that PMSS1 induces gastr...

The gastric pathogen Helicobacter pylori activates the NF-kappaB pathway in human epithelial cells via the alpha-kinase 1 (Alpk1) TIFA axis. We and others have previously shown that heptose 1,7-bisphosphate (HBP) acts as a pathogen-associated molecular pattern (PAMP). HBP is an intermediate of lipopolysaccharide (LPS) synthesis in H. pylori and oth...

Thioloxidoreductase HP0231 of Helicobacter pylori plays essential roles in gastric colonization and related gastric pathology. Comparative proteomics and analysis of complexes between HP0231 and its protein substrates suggested that several Hop proteins are its targets. HP0231 is a dimeric oxidoreductase that functions in an oxidizing Dsb (disulfid...

KD efficiency after shRNA-mediated kD of BMAL1 and HKDC1. Gene expression analysis of BMAL1 in SW480 (a) and SW620 (b) cells and HKDC1 in SW480 (c) and SW620 (d) cells after shRNA-mediated BMAL1-KD and HKDC1-KD. Gene expression is shown compared to the corresponding control gene. Mean ± SEM, n = 3. KD efficiency in SW480-shBMAL1 cells: 0.317 ± 0.00...

Metabolic activity of SW480 and SW620 control and shBMAL1 cells after oxaliplatin treatment. (a) Glycolysis of SW480 (left panel) and SW620 (right panel) control and shBMAL1 cells at three different timepoints after synchronization (18 h, 21 h, 24 h). Cells were either untreated or treated with oxaliplatin. Mean ± SEM, n = 5. (b) Glycolytic capacit...

Proliferation curve analysis. Statistical analysis was done for every timepoint of the proliferation curve to test for significant differences between the different conditions.

Changes in the core-clock of SW480 and SW620 cells lead to changes in metabolic pathways. (a) Phase-ordered, median-normalized heatmap of core-clock genes in SW480 and SW620 cells. Phase-ordering was performed based on SW480 expression data and the same ordering of genes was used for SW620 cells. (b) Phase-ordered, median-normalized heatmap of gene...

BMAL1 promoter activity in SW480 and SW620 cells and time-dependent gene expression after BMAL1-KD. (a) SW480 and (b) SW620 cells were lentivirally transduced either with an empty-vector (control) or with an shBMAL1-construct. Additionally, cells were lentivirally transduced with a Bmal1-promoter driven luciferase construct. Bioluminescence was mea...

Determination of treatment concentration for WZB117 treatment. To determine the appropriate treatment concentration with WZB117, SW480-ctrl, SW480-shBMAL1, SW620-ctrl and SW620-shBMAL1 cells were treated with different concentrations of WZB117 and the cytotoxicity was determined. Based on the calculated IC50 value, the concentration of treatment wa...

Metabolic network analysis. Expression data gained from a 24 h microarray analysis of SW480 and SW620 cells was mapped to a reconstruction of human metabolism.