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Phenotypic characterization of two neuroinvasive Toscana virus strains clinically associated with self-limited and persistent infections in human neural cells and brain organoids.
BACKGROUND: Toscana virus (TOSV), a sandfly-borne phlebovirus, is a frequent cause of viral meningitis and meningoencephalitis in Mediterranean countries during summer months. Clinical outcomes vary from self-limited disease to prolonged persistent infection lasting over 3 months, but the mechanisms underlying these differences remain unclear. In this study, we compared the pathobiological features of two clinical TOSV strains, SI-1812 (associated with self-limited disease) and INMI (associated with persistent infection), using human neural models. METHODS: Three human neural systems, DBTRG.05MG glioblastoma cells, embryonic stem cell-derived neurons, and human brain organoids (hBOs), were infected with the two TOSV strains. Viral replication, cytopathic effect, innate immune response, and viral protein expression were assessed. Furthermore, whole-genome sequencing was performed to identify strain-specific differences. RESULTS: The INMI strain showed reduced replication and cytopathic effect compared to SI-1812, supporting persistent infection in hBOs for up to 21 days. SI-1812 infection triggered a strong interferon-β response even at early stages of infection and low viral titers, whereas INMI induced a modest innate immune response in the early stages of infection, likely supporting its persistence in hBOs. The timing of viral NSs protein expression differred between the two viral strains suggesting distinct mechanisms in RIG-I activation and inflammatory response modulation. CONCLUSIONS: Distinct host-pathogen interactions underlie the divergent clinical courses of TOSV strains. The findings provide insights into mechanisms of viral persistence in the human brain and may guide future therapeutic strategies.
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Inflammatory responses revealed through HIV infection of microglia-containing cerebral organoids.
Cerebral organoids (COs) are valuable tools for studying the intricate interplay between glial cells and neurons in brain development and disease, including HIV-associated neuroinflammation. We developed a novel approach to generate microglia containing COs (CO-iMs) by co-culturing hematopoietic progenitors and inducing pluripotent stem cells. This approach allowed for the differentiation of microglia within the organoids concomitantly with the neuronal progenitors. Compared with conventional COs, CO-iMs were more efficient at generating CD45+/CD11b+/Iba-1+ microglia and presented a physiologically relevant proportion of microglia (~ 7%). CO-iMs presented substantially increased expression of microglial homeostatic and sensome markers as well as markers for the complement cascade. CO-iMs are susceptible to HIV infection, resulting in a significant increase in several pro-inflammatory cytokines/chemokines, which are abrogated by the addition of antiretrovirals. Thus, CO-iM is a robust model for deciphering neuropathogenesis, neuroinflammation, and viral infections of brain cells in a 3D culture system.
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ApoE-Isoform-Dependent SARS-CoV-2 Neurotropism and Cellular Response.
ApoE4, a strong genetic risk factor for Alzheimer disease, has been associated with increased risk for severe COVID-19. However, it is unclear whether ApoE4 alters COVID-19 susceptibility or severity, and the role of direct viral infection in brain cells remains obscure. We tested the neurotropism of SARS-CoV2 in human-induced pluripotent stem cell (hiPSC) models and observed low-grade infection of neurons and astrocytes that is boosted in neuron-astrocyte co-cultures and organoids. We then generated isogenic ApoE3/3 and ApoE4/4 hiPSCs and found an increased rate of SARS-CoV-2 infection in ApoE4/4 neurons and astrocytes. ApoE4 astrocytes exhibited enlarged size and elevated nuclear fragmentation upon SARS-CoV-2 infection. Finally, we show that remdesivir treatment inhibits SARS-CoV2 infection of hiPSC neurons and astrocytes. These findings suggest that ApoE4 may play a causal role in COVID-19 severity. Understanding how risk factors impact COVID-19 susceptibility and severity will help us understand the potential long-term effects in different patient populations.
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Techniques: Spinning organoids shed light on Zika.
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The eyeball's connected to the brain ball.
How does the human eye develop in concert with the brain to create a functioning visual system? In this issue of Cell Stem Cell, Gabriel et al. (2021) report the development of eye-like structures from forebrain organoids with light sensitivity, signal processing, and connectivity, which moves us toward answering this complex question.
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Retinal organoids: a window into human retinal development.
Retinal development and maturation are orchestrated by a series of interacting signalling networks that drive the morphogenetic transformation of the anterior developing brain. Studies in model organisms continue to elucidate these complex series of events. However, the human retina shows many differences from that of other organisms and the investigation of human eye development now benefits from stem cell-derived organoids. Retinal differentiation methods have progressed from simple 2D adherent cultures to self-organising micro-physiological systems. As models of development, these have collectively offered new insights into the previously unexplored early development of the human retina and informed our knowledge of the key cell fate decisions that govern the specification of light-sensitive photoreceptors. Although the developmental trajectories of other retinal cell types remain more elusive, the collation of omics datasets, combined with advanced culture methodology, will enable modelling of the intricate process of human retinogenesis and retinal disease in vitro.
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Reaction of the anastral mitotic apparatus of endosperm cells of the plant Leucojum aestivum with antibodies to tubulin from porcine brain as revealed by immunofluorescence microscopy.
Structures binding an antibody against tubulin from porcine brain were localized in the giant anastral mitotic apparatus of endosperm cells of the monocotyledonous plant, Leucojum aestivum, by indirect immunofluorescence microscopy. Both continuous and chromosomal spindle fibers were strongly stained. Postive fluorescence was also noted in polar cap regions and, in prometaphase stages, to some extent at the fragmented nuclear envelope. Intermingling and branching of subfiber elements was frequently noted.
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Rebutting the Ethical Considerations regarding Consciousness in Human Cerebral Organoids: Challenging the Premature Assumptions.
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Modeling the Evolution of Human Brain Development Using Organoids.
In a recent issue of Nature, Kanton et al. explore human brain evolution and development by profiling the single-cell transcriptomes and epigenomes of cerebral organoids derived from human, chimpanzee, and macaque stem cells. Their results reveal key molecular characteristics that differentiate humans and non-human primates at the earliest stages of brain development.
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Modeling Autism Spectrum Disorders with Induced Pluripotent Stem Cell-Derived Brain Organoids.
Autism spectrum disorders (ASD) are a group of complex neurodevelopmental disorders that affect communication and social interactions and present with restricted interests and repetitive behavior patterns. The susceptibility to ASD is strongly influenced by genetic/heritable factors; however, there is still a large gap in understanding the cellular and molecular mechanisms underlying the neurobiology of ASD. Significant progress has been made in identifying ASD risk genes and the possible convergent pathways regulated by these gene networks during development. The breakthrough of cellular reprogramming technology has allowed the generation of induced pluripotent stem cells (iPSCs) from individuals with syndromic and idiopathic ASD, providing patient-specific cell models for mechanistic studies. In the past decade, protocols for developing brain organoids from these cells have been established, leading to significant advances in the in vitro reproducibility of the early steps of human brain development. Here, we reviewed the most relevant literature regarding the application of brain organoids to the study of ASD, providing the current state of the art, and discussing the impact of such models on the field, limitations, and opportunities for future development.