Human brain microphysiological systems in the study of neuroinfectious disorders

Neurological infections leading to encephalitis, meningitis, and myelitis are frequently severe and prolonged neurological disorders that result in significant long-term disability. Neurological infections are produced by neurotropic pathogens, viruses, bacteria, or fungi, that can penetrate the nervous system by direct infection (e.g., trans neural or axonal transport) or hematogenous spreading. Although the laboratory diagnosis of neurological infections has improved in the past few years with the introduction of novel next-generation molecular and immunological diagnostic assays, there are still limited options for treatment. There is an urgent need for suitable models of nervous system infection that may increase our understanding of the pathogenesis of neurological infections and high-throughput screening testing of therapeutic approaches.

Microphysiological systems are 2D or 3D multicellular constructs able to mimic tissue microenvironments. This term encompasses organotypic cultures, on-a-chip technologies, scaffolds, and other 3D cultures. In this review, we will focus on 3D human brain microphysiological systems (BMPS). 3D BMPS are in-vitro culture systems, usually derived from reprogrammed somatic cells into induced pluripotent stem cells (iPSCs) or embryonic stem cells (ESC), that are later differentiated into human neuronal and glial populations. While some BMPS self-assemble to recapitulate aspects of the normal physiology of the human brain (Organoid) or can resemble the human cortex or specific regions of the brain (Zhang et al., 2021; Hopkins et al., 2021; Depla et al., 2022; Anderson et al., 2021), others represent more homogeneous models without specific regional organization(Kim et al., 2021; Leite et al., 2019; Song et al., 2019). Various studies have demonstrated BMPS can form neuronal networks, neuronal-glial interactions, electrical activity, and a cellular architecture similar to that of the human brain (Li et al., 2022; Pașca, 2018; Pamies et al., 2017). These 3D biological systems have been used to study central nervous system (CNS) development, neurotoxicity, neoplasms, neurodegenerative diseases, and more recently neurological infections (Ho et al., 2018, Barreras et al., 2022, Qian et al., 2016, Sundar et al., 2022, Lancaster et al., 2013, Pamies et al., 2020, Plummer et al., 2019, Zhong et al., 2020, Pamies et al., 2022a).

The BMPS models offer advantages over immortalized cell lines, single-layer cultures of human cells, and animal models to study neuroinfectious disease as they bypass the inter-species difference in cellular identity, signaling, and interactions, and have a closer genetic and transcriptomic profile to the human brain which can facilitate a better understanding of pathogen-cell interactions, tropism, and infection responses. BMPS allow studying interactions between various CNS cell types including neurons, astrocytes, oligodendrocytes, and in some ependymal cells (Depla et al., 2022) in co-culture in a 3D structure which closely resemble the CNS environment where the infection would take place and avoid the ethical issues of using animals in experimentation (Fan et al., 2022). BMPS have been used to study the viral tropism of various pathogens, including Zika virus (ZIKV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) during the recent epidemic and pandemic (Qian et al., 2016; Song et al., 2021; Abreu et al., 2018; Bullen et al., 2020), and have been used to assess the effect of the infection in function, structure, genetic expression and innate immune response in the CNS as well as to discover potential therapeutic targets and test antiviral therapies (Depla et al., 2022; Hopkins et al., 2021). These novel in-vitro systems have then the potential to contribute to the advancement of our understanding of neurological infections. In this review, we summarize the existing technology of BMPS used to study neurological infections, their advantages over other models, and their limitations.

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