Stem Cell Research Gives New Clues to Ebola Virus Damage to Organs – Global Biodefense

The resulting liver cell model will be a valuable tool for future studies of Ebola virus vital organ pathology and potential therapeutic interventions.

The Ebola virus (EBOV) causes serious infections in humans, and in fatal cases liver damage and dysfunction is often present, suggesting that the liver plays a decisive role in the outcome of the disease. Although the liver can be directly infected, it is not well understood how liver cells respond to Ebola virus and whether liver damage is directly caused by infection or secondary to other disease processes.

Research on the liver cell response to Ebola virus infection has been limited by the lack of appropriate cell models, but in a recent post in Stem Cell Reports, Gustavo Mostoslavsky, Elke Mühlberger and his colleagues have now harnessed stem cell biology to obtain an inexhaustible source of human liver cells, called hepatocyte-like cells (HCLs), derived from induced pluripotent stem cells. The stem cell-derived HLCs closely resembled primary liver cells and could be easily infected with Ebola virus in the laboratory.

Interestingly, the infected cultures were unable to mount a strong anti-inflammatory response to control viral spread, so the majority of cells became infected over time. Although the infected cells did not die, they turned off the genes necessary for the proper functioning of the HLC, suggesting that the viral infection directly disrupts liver function. Additionally, Ebola virus-infected immune cells could transfer the virus to HLCs in co-cultures, i.e. when grown in the same dish, suggesting that infected immune cells may act as viral shuttles in patients.

“This is the first time that such a platform (liver cells produced from stem cells) has been used to study Ebola virus infection. Our results provide a first insight into the host response of primary human liver cells to Ebola virus infection,” Mostoslavsky and Mühlberger said of the study. “Our study shows that key liver cell functions are compromised by Ebola virus infection. It also suggests that these highly pathogenic viruses have evolved a mechanism that prevents an early antiviral response in the infected organism. This gives them enough time to replicate and cause damage.

Transmission electron microscopy of human hepatocyte-like cells derived from Ebola virus-infected iPSCs. Filamentous Ebola virus particles are released from infected cells (arrows). Credit: John G. Bernbaum, Integrated Research Facility, Division of Clinical Research, NIH/NIAID

The use of co-culture systems, such as the one demonstrated in this study, can help determine which cell types in the liver are responsible for specific host responses, helping to define an intrinsic disease signature to the cell difficult to discern as a whole. – organ environment. The data presented supports that genes associated with liver function are disrupted in EBOV-infected hepatocytes. Future studies using this platform can help identify how EBOV impairs liver function during disease progression and inform the development of therapeutic interventions that can universally prevent EBOV mortality.

“Ebola virus outbreaks have very high mortality and have a huge impact on health care. Understanding how the virus causes tissue damage is essential to help design new therapeutic interventions or prevent the spread,” Mostoslavsky and Mühlberger said.

Twenty researchers participated in the study, including scientists from Boston University School of Medicine, National Emerging Infectious Diseases Laboratories (NEIDL)Center for Regenerative Medicine (CReM), Boston Medical Center, Massachusetts Institute of Technology, National Institute for Allergy and Infectious Disease, National Institutes of Health, Koch Institute for Integrative Cancer Research, Broad Institute, Department of Medicine at Brigham and Women’s Hospital, and the Howard Hughes Medical Institute.

Ebola virus infection induces delayed type I IFN response in bystander cells and shutdown of key liver genes in iPSC-derived human hepatocytes. Stem Cell Reports, September 8, 2022.

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