Biology subjects

Brinkmann, V.

Publications and source records attributed to Brinkmann, V..

4 recordsLinked to original sources

bioRxiv2018

Transition of Wnt signaling microenvironment delineates the squamo-columnar junction and emergence of squamous metaplasia of the cervix

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 types and what factors contribute to metaplasia. Here we show that the cervical squamo-columnar junction derives from two distinct stem cell lineages that meet at the TZ. In contrast to the prevailing notion, our analysis of cervical tissue showed that the TZ is devoid of any locally restricted, specialized stem cell population, which has been implicated as precursor of both cervical squamous cell carcinoma and adenocarcinoma. Instead, we reveal that these cancers originate from two separate stem cell lineages. We show that the switch in the underlying Wnt signaling milieu of the stroma is a key determinant of proliferation or quiescence of epithelial stem cell lineages at the TZ. Strikingly, while the columnar lineage of the endocervix is driven by Wnt signaling, the maintenance of squamous stratified epithelium of the ectocervix and emergence of squamous metaplasia requires inhibition of Wnt signaling via expression of Dickkopf2 (Dkk2) in the underlying stroma. Moreover, Notch signaling is required for squamous cell stratification. Thus, our results indicate that homeostasis at the TZ is not maintained by a transition from one epithelial type to another but rather results from alternative signals from the stromal compartment driving the differential proliferation of the respective cell lineages at the squamo-columnar junction.

cancer biology↗

bioRxiv2017

Single-cell RNA-sequencing redefines blood cell type classification in mosquitoes

Mosquito blood cells are ancestral immune cells that help control infection by vector-borne pathogens. Despite their importance, little is known about mosquito blood cell biology beyond the ambiguous morphological and functional criteria used for their classification. Here we combined the power of single-cell RNA-sequencing, imaging flow cytometry and single-molecule RNA hybridization to analyze blood cells of the malaria mosquito Anopheles gambiae. By demonstrating that blood cells express nearly half of the mosquito transcriptome, our dataset represents an unprecedented view into their transcriptional machinery. Analyses of differentially expressed genes identified transcriptional signatures of two distinct cell types that challenge the current morphology-based classification of these cells. We further demonstrated an active transfer of a cellular marker between blood cells that confounds their identity. We propose that cell-to-cell exchange is broadly relevant for cell type classification and may account for the remarkable cellular diversity observed in nature.

immunology↗

bioRxiv2017

Mosquito lipids regulate Plasmodium sporogony and infectivity to the mammalian host

Malaria is a fatal human parasitic disease transmitted by a mosquito vector. The evolution of within-host malaria virulence has been the focus of many empirical and theoretical studies. However, the vectors contribution to virulence evolution is not well understood. Here we explored how within-vector resource exploitation impacts evolutionary trajectories of within-host Plasmodium virulence. We developed a nested model of within-vector dynamics and malaria epidemiology, which predicted that non-competitive resource exploitation within-vector restricts within-host parasite virulence. To validate our model, we experimentally manipulated mosquito lipid trafficking and gauged within-vector parasite development, within-host infectivity and virulence. We found that mosquito-derived lipids determine within-host parasite virulence by shaping development and metabolic activity of transmissible sporozoites. Our findings uncover the role of within-vector environment in regulating within-host Plasmodium virulence and identify Plasmodium metabolic traits that may contribute to the evolution of malaria virulence.

microbiology↗

bioRxiv2017

ALPK1 And TIFA Dependent Innate Immune Response Triggered By The Helicobacter Pylori Type IV Secretion System

Activation of transcription factor NF-{kappa}B is a hallmark of infection with the gastric pathogen Helicobacter pylori and associated with inflammation and carcinogenesis. Genome-wide RNAi screening revealed numerous hits involved in H. pylori-, but not IL-1{beta}- and TNF-- dependent NF-{kappa}B regulation. Pathway analysis including CRISPR/Cas9-knockout and recombinant protein technology, immunofluorescence microscopy, immunoblotting, mass spectrometry and mutant H. pylori strains, identified the H. pylori metabolite D-glycero-{beta}-D-manno-heptose 1,7-bisphosphate ({beta}HBP) as a cagPAI type IV secretion system (T4SS)-dependent effector of NF-{kappa}B activation in infected cells. Upon pathogen-host cell contact, TIFA forms large complexes (TIFAsomes) including interacting host factors, such as TRAF2. NF-{kappa}B activation, TIFA phosphorylation as well as TIFAsome formation depended on a functional ALPK1 kinase, highlighting the ALPK1-TIFA axis as core of a novel innate immune pathway. ALPK1-TIFA-mediated NF-{kappa}B activation was independent of CagA protein translocation, indicating that CagA translocation and HBP delivery to host cells are distinct features of the pathogens T4SS.

molecular biology↗