Ebola virus infection (red) spreads along the epithelial edge of a human colonic iPSC-derived organoid, where GFP-CDX2 (green) highlights the organized gut epithelium and DAPI (blue) reveals the nuclear architecture. Scale bar = 100 μm. The image was generated by E. Y. Flores. 

Marburg Virus

Researchers Discover How Ebola and Marburg Disrupt the Gastrointestinal Tract

A new study first-authored by Elizabeth Yvonne Flores, PhD, a recent graduate from Boston University Chobanian & Avedisian School of Medicine, BU’s National Emerging Infectious Diseases Laboratories (NEIDL) and the Center for Regenerative Medicine (CReM) of BU and Boston Medical Center, sheds light on the mechanisms behind this damage. The study found that both EBOV and MARV are capable of infecting and replicating within human gut epithelial cells and that the viruses interfere with the cells’ ability to regulate fluid secretion, mirroring the severe symptoms observed in patients.

“This research enhances our understanding of how filovirus infections damage the gut and identifies potential cellular pathways for targeted treatments,” explains co-corresponding author Elke Mühlberger, PhD, professor of virology, immunology & microbiology and an investigator at BU’s NEIDL. “It also highlights how useful iPSC-derived organoids are for studying viral diseases.”

To study actual human gut tissue in a controlled environment, the researchers grew organoids–miniature, 3D structures that mimic human intestinal and colonic tissue from induced pluripotent stem cells (iPSCs), a type of stem cell created in a lab from regular adult cells, like skin or blood cells. They then successfully infected these “mini-guts” with EBOV and MARV, observing that the viruses could replicate within the tissue.

By analyzing gene activity signatures in the infected organoids, they discovered that organoids resembling the small intestine and those resembling the colon responded differently to infection, with more severe dysfunction in the colonic organoids. The infections disrupted key signaling pathways involved in ion and fluid transport in the gut and damaged the structure of the gut lining, including the apical (the outermost surface of a cell) and junctional (the connection between cells) components that control what passes through the intestinal wall. These changes may help explain how these viruses cause the massive fluid loss that leads to life-threatening diarrhea. They also found the infected mini-guts showed a delayed innate immune response, specifically in the production of interferon-stimulated genes, which usually help fight off viruses. 

“The organoid platform successfully captures key features of human GI pathology, making it a powerful tool for future research to understand host-pathogen interactions better and identify potential therapeutic targets to treat these deadly diseases,” said co-corresponding author Gustavo Mostoslavsky, MD, PhD, professor of medicine and virology, immunology & microbiology at the school and co-director of CReM. 

These findings appear online in the journal PloS Pathogens.

This work was supported by the National Institutes of Health (NIH) National Institute of Allergy and Infectious Diseases (R21AI167369 to GM and EM; https://www.niaid.nih.gov), and by the Howard Hughes Medical Institute Emerging Pathogens Initiative (Agreement dated 9/16/22; Lead Investigator Anna Pyle; GM and EM; https://www.hhmi.org). Histopathology analyses were supported by NIH S10 instrumentation awards (S10OD030269 and S10OD026983). EYF was supported by the Boston University Clinical and Translational Science Institute (BU CTSI) TL1 Predoctoral Fellowship in Regenerative Medicine (TL1TR001410 to EYF) and an NIH NIAID Predoctoral Fellowship (F31AI183803 to EYF). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.