Modelling host-Trypanosoma brucei gambiense interactions in vitro using human induced pluripotent stem cell-derived cortical brain organoids

The generation of human brain organoids from stem cells has provided unprecedented insights into the mechanisms underlying brain development and holds the promise to study infections affecting the brain, including sleeping sickness. However, brain organoids have not yet been exploited to study this disease. Sleeping sickness is caused by the extracellular parasite Trypanosoma brucei and is associated with neuroinflammation and neuropsychiatric disorders, including disruption of sleep/wake patterns, and is now recognised as a circadian disorder. Sleeping sickness is traditionally studied using murine models of infection due to the lack of alternative in vitro systems that fully recapitulate the cellular diversity and functionality of the brain. This challenge can now be overcome with the use of stem cell-derived human brain organoids generated in vitro. These brain organoids represent cutting-edge tools that can offer invaluable insights into the mechanisms of brain development and are beginning to be exploited to study host-pathogen interactions as an alternative to murine models of infection. The aim of this study is to develop a much-needed in vitrosystem that reduces and replaces live animals for the study of infections in the central nervous system, using sleeping sickness as a model infection. The use of human brain organoids to study neuroinflammation induced by African trypanosomes has not been implemented before, with only a limited number of studies reporting the utility of the organoids to study infections such as Zika Virus (ZIKV), toxoplasmosis and malaria, and SARS2-cov-19. We propose that the adoption of organoid systems will be beneficial to researchers studying mechanisms of brain infection by protozoan parasites. Furthermore, organoid systems have the potential to be used to study other parasites that affect the brain, including neurocysticercosis, significantly reducing the number of animals undergoing moderate and/or severe protocols associated with the study of neuroinflammation and brain infections.