Publications

Recent Highlights

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• Kapalczynska M, Lin M, Maertzdorf J, Heuberger J, Muellerke S, Zuo X, Vidal R, Shureiqi I, Fischer AS, Sauer S, Berger H, Kidess E, Mollenkopf HJ, Tacke F, Meyer TF and Sigal M. BMP feed-forward loop promotes terminal differentiation in gastric glands and is interrupted by H. pylori-driven inflammation.
  Nature Communications (2022).
• Koster S, Gurumurthy RK, Kumar N, Prakash PN, Dhanraj J, Bayer S, Berger H, Kurian SM, Drabkina M, Mollenkopf HJ, Goosmann C, Brinkmann V, Nagel Z, Mangler M, Meyer TF and Chumduri C. Modelling Chlamydia and HPV co-infection in patient-derived ectocervix organoids reveals distinct cellular reprogramming. Nature Communications (2022).
• Berger H and Meyer TF. Mechanistic dissection unmasks colibactin as a prevalent mutagenic driver of cancer. Cancer Cell (2021)
• Wölffling S, Daddi AA, Aki Imai-Matsushima A, Fritsche K, Goosmann C, Traulsen J, Lisle R, Schmid M, Reines MdM, Pfannkuch L, Brinkmann V, Bornschein J, Malfertheiner P, Ordemann J, Link A, Meyer TF* and Boccellato F*. EGF and BMPs govern differentiation and patterning in human gastric glands. Gastroenterology (2021)
• Iftekhar A, Berger H, Bouznad N, Heuberger J, Boccellato F, Dobrindt U, Hermeking H, Sigal M and Meyer TF. Genomic aberrations after short-term exposure to colibactin-producing E. coli transform primary colon epithelial cells. Nature Communications (2021)
• Chumduri C, Gurumurthy RK, Berger H, Dietrich O, Kumar N, Koster S, Brinkmann V, Hoffmann K, Drabkina M, Arampatzi P, Son D, Klemm U, Mollenkopf HJ, Herbst H, Mangler M, Vogel J, Saliba AE and Meyer TF. Opposing Wnt signals regulate cervical squamocolumnar homeostasis and emergence of metaplasia. Nature Cell Biology (2021)
• Dziubańska-Kusibab PJ, Berger H, Battistini F, Bouwman BAM, Iftekhar A, Katainen R, Cajuso T, Crosetto N, Orozco M, Aaltonen LA and Meyer TF. Colibactin DNA damage signature indicates mutational impact in colorectal cancer. Nature Medicine (2020)
• Xavier A, Al-Zeer MA, Meyer TF and Daumke O. hGBP1 Coordinates Chlamydia Restriction and Inflammasome Activation through Sequential GTP Hydrolysis. Cell Reports (2020)
• Hoffmann K, Berger H, Kulbe H, Thillainadarasan S, Mollenkopf HJ, Zemojtel T, Taube E, Darb-Esfahani S, Mangler M, Sehouli J, Chekerov R, Braicu EI, Meyer TF and Kessler M. Stable expansion of high-grade serous ovarian cancer organoids requires a low-Wnt environment.
  EMBO J (2020)
• Harnack C, Berger H, Antanaviciute A, Vidal R, Sauer S, Simmons A, Meyer TF, and Sigal M. R-spondin 3 promotes stem cell recovery and epithelial regeneration in the colon. Nature Communications (2019)
• Sigal M, Reines MdM, Müllerke S, Fischer C, Kapalczynska M, Berger H, Bakker ERM, Mollenkopf H-J, Rothenberg ME, Wiedenmann B, Sauer S and Meyer TF. R-spondin-3 induces secretory, antimicrobial Lgr5+ cells in the stomach. Nature Cell Biology (2019)
• Pfannkuch L, Hurwitz R, Traulsen J, Sigulla J, Poeschke M, Matzner L, Kosma P, Schmid M and Meyer TF. ADP heptose, a novel pathogen-associated molecular pattern identified in Helicobacter pylori. FASEB J (2019)
• Kessler M, Hoffmann K, Fritsche K, Brinkmann V, Mollenkopf HJ, Thieck O, Teixeira da Costa AR, Braicu EI, Sehouli J, Mangler M, Berger H and Meyer TF. Chronic Chlamydia infection in human organoids increases stemness and promotes age-dependent CpG methylation. Nature Communications (2019)
• Rother M, Gonzalez E, Teixeira da Costa AR, Wask L, Gravenstein I, Pardo M, Pietzke M, Gurumurthy RK, Angermann J, Laudeley R, Glage S, Meyer M, Chumduri C, Kempa S, Dinkel K, Unger A, Klebl B, Klos A and Meyer TF. Combined Human Genome-wide RNAi and Metabolite Analyses Identify IMPDH as a Host-Directed Target against Chlamydia Infection. Cell Host & Microbe (2018)
• Boccellato F, Woelffling S, Imai-Matsushima A, Sanchez G, Goosmann C, Schmid M, Berger H, Morey P, Denecke C, Ordemann J and Meyer TF. Polarised epithelial monolayers of the gastric mucosa reveal insights into mucosal homeostasis and defence against infection. Gut (2018)
• Morey P, Pfannkuch L, Pang E, Boccellato F, Sigal M, Imai-Matsushima A, Dyer V, Koch M, Mollenkopf H-J, Schlaermann P, Meyer TF. Helicobacter pylori Depletes Cholesterol in Gastric Glands to Prevent Interferon gamma Signaling and Escape the Inflammatory Response. Gastroenterology (2017)
• Zimmermann S, Pfannkuch L, Al-Zeer MA, Bartfeld S, Koch M, Liu J, Rechner C, Soerensen M, Sokolova O, Zamyatina A Kosma P, Maurer A P, Glowinski F, Pleissner K P, Schmid M, Brinkmann V, Karlas A, Naumann M, Rother M, Machuy N and Meyer TF. ALPK1- and TIFA-Dependent Innate Immune Response Triggered by the Helicobacter pylori Type IV Secretion System. Cell Reports (2017)
• Sigal M, Logan CY, Kapalczynska M, Mollenkopf H-J, Berger H, Wiedenmann B, Nusse R, Amieva MR and Meyer TF. Stromal R-spondin orchestrates gastric epithelial stem cells and gland homeostasis. Nature (2017)
• Karlas A, Berre S, Couderc T, Varjak M, Braun P, Meyer M, Gangneux N, Karo-Astover L, Weege F, Raftery M, Schoenrich G, Klemm U, Wurzlbauer A, Bracher F, Merits A, Meyer TF and Lecuit M. A human genome-wide loss-of-function screen identifies effective chikungunya antiviral drugs. Nature Communications (2016)
• Schlaermann P, Toelle B, Berger H, Schmidt SC, Glanemann M, Ordemann J, Bartfeld S, Mollenkopf HJ and Meyer TF. A novel human gastric primary cell culture system for modelling Helicobacter pylori infection in vitro. Gut (2016)

History of the Laboratory and Achievements

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Genetic basis of microbial virulence and underlying mechanisms (1978 – 1998)

 

• Replication of circular double-stranded phage DNA in vitro, revealing basic insights into DNA amplification mechanisms even prior to the invention of PCR. E.g., Meyer et al.,
  Nature (1979) and Meyer et al.,
  Nature (1982).
• Cloning of the first Neisseria gonorrhea gene, pilin. This work established the first paradigm of a complex genetic system for antigenic variation in bacteria. E.g., Meyer et al., Cell (1982), Haas et al., Cell (1986), Haas et al., PNAS (1987) and Gibbs et al., Nature (1989).
• The discovery of a variable pentameric nucleotide repeat sequence (later referred to as slipped strand mispairing) that defines bacterial translational reading frame in otherwise intact genes. In Neisseria gonorrhea, it characterizes the family of opacity associated proteins (Opa). E.g., Stern et al., Cell (1984), Stern et al., Cell (1986) and Stern et al., Mol Microbiol (1987).
• Cloning of the gene encoding the IgA protease of Neisseria gonorrhea, thus constituting the paradigm of autotransporter secretion in gram-negative bacterial species, later also referred to as type V secretion. E.g., Halter et al., EMBO J (1984) and Pohlner et al., Nature (1987).
• The mechanistic assessment of the autotransporter system enabled the secretion of heterologous proteins from recombinant E. coli, establishing a paradigm for similar secretion systems explored by other groups. Insight into the critical role of periplasmic oxidoreductases in protein folding (DsbA) to facilitate secretion. E.g., Klauser et al., EMBO J (1990), Klauser et al., EMBO J (1992), Klauser et al., J Mol Biol (1993) and Jose et al., Mol Microbiol (1995).
• Cloning of the large capsule gene cluster of serogroup B, allowing insight into pathogenesis by Neisseria meningitidis. E.g., Frosch et al., PNAS (1989).
• The identification of mosaic gene structure in the IgA gene locus of Neisseria and key determinants of natural transformation competence. This sheds a light on microbial diversity and genome evolution. E.g., Halter et al., EMBO J (1989), Frosch et al., FEMS Microbiol Lett (1992), Facius et al., Mol Microbiol (1993), Fussenegger et al., Mol Microbiol (1996) and Fussenegger et al., Mol Microbiol (1996).

From insights into host cell mechanisms towards host-directed therapy (1991 – 2019)

 

• The characterization of the variable Neisseria Opa proteins as cellular invasins with different cell tropisms marked the beginning of investigations into the involvement of host factors in the process of bacterial infections. E.g., Makino et al., EMBO J (1991), Kupsch et al., EMBO J (1993), Gray-Owen et al., EMBO J (1997) and Billker et al., EMBO J (2002).
• The retractile type 4 pili produced by the pathogenic Neisseria species displays crucial functions in cell adherence, pilus assembly, and natural transformation. E.g., Rudel et al., Mol Microbiol (1992) and Rudel et al., Nature (1995).
• Binding of the gonococcal pili to human epithelial cells elicited a so far unknown anti-phagocytic feature, leading to the formation of cortical plaques and prevention of the internalization of attached bacteria. E.g., Boettcher et al., PLoS Biol (210).
• The neisserial PorB is recognized as a GTP/ATP modulated porin that translocates into host cells, where it associates with mitochondria to modulate the apoptosis of infected cells. E.g., Rudel et al., Cell (1996), Müller et al., EMBO J (1999), Müller et al., EMBO J (2000) and Müller et al., EMBO J (2002).
• Using pathogenic Neisseria species, several new pathways could be identified that were intimately involved in bacterial internalization (host cell invasion) and inflammatory responses. E.g., Grassmé et al., Cell (1997), Naumann et al., J Exp Med (1997), Hauck et al., EMBO J (1998) and Naumann et al., J Exp Med (1998).
• Host cell survival and intracellular vesicular trafficking upon infection with the obligate intracellular bacterium Chlamydia trachomatis, particularly the modulation of signaling routes involved in the stress response to endocytic maturation and Golgi compartment function. E.g., Mäurer et al., PLoS Pathog (2007), Heuer et al., Nature (2009), Gurumurthy et al., Sci Signal (2010), Mehlitz et al., J Cell Biol (2010), Al-Younes et al., Autophagy (2011) and Al-Zeer et al., Autophagy (2013).
• Large-scale analyses of host factors engaged in viral and intracellular bacterial pathogen propagation were conducted by applying RNAi technology in human epithelial cells. The identified hits could potentially be used as targets for a novel type of anti-infective therapy. Pathogens studied: Influenza virus, Chikungunya virus and the bacterium Chlamydia trachomatis. E.g., Karlas et al., Nature (2010), Tripathi et al., Cell Host Microbe (2015), Karlas et al., Nat Comm (2016), Rother et al., Cell Host Microbe (2018) and Lesch et al., PLoS Pathog (2019).

Impact of chronic bacterial infections on the emergence of human cancer (2000 – ongoing)

 

• With the recognition of Helicobacter pylori’s cagPAI type 4 secretion system (T4SS) as a significant virulence attribute, the laboratory was at the forefront of establishing a molecular basis for its function as an inflammatory and potentially transforming determinant. In particular, signaling routes mediated by the CagA effector protein and metabolites of LPS synthesis enable bacterial survival and persistence. E.g., Backert et al., Cell Microbiol (2000), Selbach et al., J Biol Chem (2002), Selbach et al., EMBO J (2003), Bauer et al., Cell Host Microbe (2012), Koch et al., PNAS (2012), Belogolova et al., Cell Microbiol (2013), Bielig et al., PLoS Pathog (2014), Koeppel et al., Cell Rep (2014), Zimmermann et al., Cell Rep (2017) and Pfannkuch et al., FASEB J (2019).
• We discovered the Helicobacter pylori enzyme glucosyl-a-cholesterol transferase that causes depletion of host cell cholesterol and inactivate lipid raft-dependent cytokine receptors. This mechanism establishes immune protected niches on the mucosal surface, which allow H. pylori to persist despite the intense inflammatory response. The observations suggest a putative mechanism by which H. pylori induces a precancerous condition and explains the failure of previous vaccination efforts. E.g., Lebrun et al., J Biol Chem (2006), Wunder et al., Nat Med (2006), Aebischer et al., Gut (2008) and Morey et al., Gastroenterology (2018).
• For studying the mechanisms of Helicobacter pylori infection and cell transformation in vitro, it was necessary to establish a suitable epithelial model. A breakthrough was obtained upon the establishment of gastric epithelial organoids and mucosoids that combine quasi-indefinite growth with the reproduction of in-vivo-like infection conditions. E.g., Boxberger et al., Eur J Cell Biol (1993), Boxberger et al., Epithelial Cell Biol (1994), Schlaermann et al., Gut (2016) and Boccellato et al., Gut (2018). A similar organoid model was established to study Salmonella Paratyphi A infections of gallbladder cells. Sepe LP et al., mBio (2020).
• We established novel mouse models, utilizing state-of-the-art genetic lineage tracing systems and in situ detection of single molecules, to study damage and regeneration of the epithelium under normal, abnormal and infected conditions. These models provide deep insight into the remodeling capacity and plasticity of epithelial stem cells and the emergence of their respective cancers. We identified, for example, the involvement of inflammatory cytokines and morphogens, such as R-spondin, in gastric carcinogenesis. E.g., Sigal et al., Nature (2017), Sigal et al., Nat Cell Biol (2019), Harnack et al., Nat Comm (2019), Chumduri et al., Nat Cell Biol (2021), Wölffling et al., Gastroenterology (2021) and Kapalczynska,et al., Nat Comm (2022).
• We assess similar processes in other bacterial species, such as Chlamydia trachomatis in the female genital tract. We have elucidated infection-mediated mechanisms of DNA damage, pro-proliferation, anti-apoptosis and favorable metabolism in host cells, demonstrating the cancer-promoting potential of pathogenic Chlamydia . E.g., Chumduri et al., Cell Host Microbe (2013), González et al., Nat Comm (2014), Chumduri et al., Nat Rev Mol Cell Biol (2016) and Zadora et al., Cell Rep (2019).
• To better understand Chlamydia trachomatis infections of the female genital tract and their potential carcinogenic consequences, primary tissue and organoid models have been established. Human fallopian tube and cervical epithelia are considered to provide the precursors of ovarian cancer and cervical cancer, respectively. We identified, for example, the involvement of morphogens, such as Wnt, DKK2, Notch and BMP. E.g., Kessler et al., Am J Pathol (2012), Kessler et al., Nat Comm (2015), Hoffmann et al., EMBO J (2020), Chumduri et al., Nat Cell Biol (2021) and Koster et al., Nat Comm (2022).
• Using advanced techniques and thorough bioinformatics analyses, we aim to identify genetic signatures that bacterial pathogens leave behind in human cancers, proving a causative role in carcinogenesis. Two very recent highlights of this ambitious research show that E. Coli‘s genotoxin, colibactin, causes double-strand breaks, resulting in a specific pattern of mutations in murine and human cells as well as in human colorectal cancer.
  Dziubańska-Kusibab et al. Nature Medicine (2020) and Iftekhar et al. Nature Comm (2021) .

Complete List

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For all publications from the Thomas F. Meyer lab, please search via PubMed or Google Scholar.