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Modeling infectious diseases of the central nervous system with human brain organoids

      Bacteria, fungi, viruses, and protozoa are known to infect and induce diseases in the human central nervous system (CNS). Modeling the mechanisms of interaction between pathogens and the CNS microenvironment is essential to understand their pathophysiology and develop new treatments. Recent advancements in stem cell technologies have allowed for the creation of human brain organoids, which more closely resembles the human CNS microenvironment when compared to classical 2-dimensional (2D) cultures. Now researchers can utilize these systems to investigate and reinvestigate questions related to CNS infection in a human-derived brain organoid system. Here in this review, we highlight several infectious diseases which have been tested in human brain organoids and compare similarities in response to these pathogens across different investigations. We also provide a brief overview of some recent advancements which can further enrich this model to develop new and better therapies to treat brain infections.

      Abbreviations:

      2D (2-dimensional), 3D (3-dimensional), ACE2 (Angiotensin-converting enzyme 2), AD (Alzheimer's disease), APOE4/4 e4 (Allele of apolipoprotein E), AQ (Amodiaquine dihydrochloride dihydrate), BBB (Blood-brain barrier), B-CSF-B (Blood- cerebrospinal fluid barrier), BDNF (Brain-derived neurotrophic factor), ChP (Choroid plexus), CJD (Creutzfeldt–Jakob Disease), CNS (Central nervous system), COVID 19 (Coronavirus disease 2019), CSF (Cerebrospinal fluid), DEG (Differentially expressed genes), EGFR (Epidermal growth factor receptor), ESC (Embryonic stem cell), ETV2 (ETS variant 2), FGF2 (Fibroblast growth factor 2), GBS (Guillain-Barre syndrome), GI (Gastrointestinal), GO (Gene ontology), HAND (HIV-1-associated neurocognitive disorders), HCM (Human cerebral malaria), HCMV (Human cytomegalovirus), hESCs (Human embryonic stem cells), HEV (Hepatitis E virus), HH (Hippeastrine hydrobromide), hiPSCs (Human induced pluripotent stem cells), HIV-1 (Human Immunodeficiency Virus), hPSCs (Human pluripotent stem cells), HSE (Herpes simplex encephalitis), HSV-1 (Human herpes simplex virus-1), IFN (Interferon), ISGs (Interferon stimulated genes), JCV (Human polyomavirus JC), Mtb (Mycobacterium tuberculosis), NPC (Neural progenitor cells), NRG-1 (Neuregulin-1), NRP1 (Natriuretic peptide receptor 1), NS2A (Nonstructural protein 2A), NS5 (Nonstructural protein 5), NSC (Neural stem cells), PDGFRα (Platelet-derived growth factor receptor alpha), PPS (Pentosan polysulfate), SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2), sCJD (Sporadic CJD), SVZ (Subventricular zone), TLR3 (Toll-like receptor 3), vsiRNAs (Virus-derived small interfering RNAs), VZ (Ventricular zone), WHO (World Health Organization), ZIKV (Zika-virus))
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