Human Brain Organoids as an In Vitro Model System of Viral Infectious Diseases

Abstract

Brain organoids, or brainoids, have shown great promise in the study of central nervous system (CNS) infection. Modeling Zika virus (ZIKV) infection in brain organoids may help elucidate the relationship between ZIKV infection and microcephaly. Brain organoids have been used to study the pathogenesis of SARS-CoV-2, human immunodeficiency virus (HIV), HSV-1, and other viral infections of the CNS. In this review, we summarize the advances in the development of viral infection models in brain organoids and their potential application for exploring mechanisms of viral infections of the CNS and in new drug development. The existing limitations are further discussed and the prospects for the development and application of brain organs are prospected.

Keywords: brain organoid; brainoid; infection; model system; pathogenesis; prion; virus.

Figure 1

Application of induced pluripotent stem cells (iPSCs) and iPSCs-derived system. The enhanced culture and differentiation of iPSCs will improve the efficiency and quality of the organoids derived from iPSCs. The use of gene editing techniques such as CRISPR-Cas9 and specific small molecules will allow the generation of terminally differentiated patient cells and isogenic lines, reducing background genetic variation, and broadening the range of cells available for drug screening. Targeted differentiation schemes can be used to generate neural progenitor cells, which can be further induced into specific populations of neurons or glial cells. Two-dimensional (2D) cultures produce highly enriched cell populations to study the role of drugs in specific cell types. Three-dimensional (3D) cultures produce organoids that are similar in organization and function to the developing human brain and are used in high-throughput drug screening, genetic research, and infectious disease modeling, and to drive the development of precision medicine.

Figure 2

SARS-CoV-2 entry into the central nervous system. Viruses in the blood may infect peripheral immune cells. These infected white blood cells can cross the blood-brain barrier (BBB), which is made up of special tight junctions between endothelial cells, pericytes, and astrocytes. In addition, the virus may cross the BBB, which may be modified by cytokines, or enter the cerebrospinal fluid (CSF) through direct interaction with the endothelium. Both mechanisms lead to changes in brain homeostasis and increase the production of cytokines in the central nervous system.