Infection and host cell tropism in the gut - organoids as model

Organoids are rapidly advancing new models, comprised of 3-dimensional (3D) multicellular primary cell cultures that closely mimic the in vivo organization of different cell types. Organoids have been used to model many diseases, including genetic disease, cancer, and infectious diseases. We use adult stem cell-derived organoids to analyze the molecular basis of innate immune signaling in the epithelium and to study infections of the gastrointestinal tract. 
We generated a biobank of human and murine organoids covering 6 sites from stomach to colon. RNA-sequencing showed that the tissue identity is conserved in the adult stem cells. Moreover, components of the epithelial innate immune sensing, such as toll like receptors, are part of the tissue identity and highly organized along the gastrointestinal tract. This organization is for a large part determined by developmental processes rather than by environmental factors. 
Severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) infection primarily affects the lung but can also cause gastrointestinal symptoms. In vitro experiments confirmed that SARS-CoV-2 robustly infects intestinal epithelium. However, data on infection of adult gastric epithelium is sparse and a side-by-side comparison of the infection in the major segments of the gastrointestinal tract is lacking. We provide this direct comparison in organoid-derived monolayers and demonstrate that SARS-CoV-2 robustly infects intestinal epithelium, while gastric epithelium is resistant to infection. RNA sequencing and proteome analysis pointed to ACE2 as critical factor, and indeed, ectopic expression of ACE2 increased susceptibility of gastric organoid-derived monolayers to SARS-CoV-2. ACE2 expression pattern in patient gastrointestinal biopsies mirror SARS-CoV-2 infection levels in monolayers. Thus, local ACE2 expression limits SARS-CoV-2 expression in the GI tract to the intestine, suggesting that the intestine, but not the stomach is likely to be important in viral replication and possibly transmission.

Sina Bartfeld studied Biology in Hamburg, Melbourne and Berlin. In her PhD thesis at the Max Planck Institute for Infection Biology in Berlin, she identified ALPK1 as a central signaling molecule in the innate immune response to bacteria. During her postdoctoral time in the lab of Hans Clevers in the Netherlands, she pioneerd the use of patient-derived organoids for infection biology and contributed to the understanding of stem cells in the stomach. From 2015 to 2021, she led a junior group at the University of Würzburg. In September 2021, she joined the Technical University Berlin as full professor to head the Department of Medical Biotechnology and to be part of „Der Simulierte Mensch“, a joint research center of Charite and TU Berlin. 
The Bartfeld lab is interested in the molecular basis of epithelial diseases, especially host cell responses to infections of the gastrointestinal tract. While asking basic mechanistic questions in infection and innate immune signaling, the group also strives to develop and improve in vitro models. Sina Bartfeld serves as Co-Speaker for „Der Simulierte Mensch“, as vice speaker for the the DFG GRK2157, developing 3D models for infection research, on the board of the German Stem Cell Network, on the board of the Working group Gastrointestinal Infections of the German Society for Hygiene and Microbiology, on the editorial boards of the Journal of Molecular Medicine and the Journal Cellular Microbiology, and as member of the Working Group Gene Technology Report. 

Moderation: Professorin Dr. Anca Dorhoi