Mechanisms Associated with Virus-Induced Microcephaly Revealed

A research team from the Institute of Molecular Biotechnology of the Austrian Academy of Sciences demonstrated that different viruses can lead to brain malformations through diverse mechanisms by using human brain organoid models. The results were published in Cell Stem Cell.

Their findings reveal the mechanisms linked to virus-induced microcephaly using a human brain organoid model derived from human pluripotent stem cells. "The two major difficulties in researching these conditions are, first, the delicate topic of testing noxious effects on fetal brain development during pregnancy which, understandably, prevents direct research on human fetuses, and second, the unsuitability of laboratory animal models, as they are neither the natural hosts of the viruses nor do they represent an accurate model of human brain development,” explains first author Veronica Krenn.

“To this end, our group was able to compare 3D human brain organoid models infected with different viruses. These infection models give us the closest possible insight into the human brain developmental outcomes of the viruses we study, and help us dissect the underlying structural, cellular, transcriptional and immunological parameters," Krenn adds. 

Through transcriptional profiling, the team shows a unique feature of HSV-1 infection in organoids, namely a propensity to impair their neuroepithelial identity. Another major finding is that, although both ZIKV and HSV-1 attenuate the Type I interferon immune response system in organoids, they appear to do so through different mechanisms, as is made evident by rescue experiments using distinct Type I IFNs.

The findings highlight the distinct paths used by various TORCH viruses to cause microcephaly and reveal complex cellular immune defenses, such as a neuroprotective role of various Type I IFN responses. The importance of these findings also resides in their unique observation in 3D brain organoid cultures, and not in 2D culture systems, thus stressing the superiority of HBO models in reproducing virus-induced neuropathological conditions and their relevance in studying the mechanisms of viral infections.