SARS-CoV-2 infects human brain organoids causing cell death and loss of synapses that can be rescued by treatment with Sofosbuvir

Mesci, Pinar; Souza, Janaína Sena de; Martin-Sancho, Laura; Macia, Ángela; Saleh, Aurian; Yin, Xin; Snethlage, Cedric E; Adams, Jason W; Avansini, Simoni Helena; Herai, Roberto Hirochi; Almenar-Queralt, Angels; Pu, Yuan; Szeto, Ryan A.; Goldberg, Gabriela; Bruck, Patrick T.; Papes, Fábio; Chanda, Sumit K.; Muotri, Alysson R.

doi:10.1371/journal.pbio.3001845

Cited by 36 publications

(47 citation statements)

References 90 publications

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“…Our findings, in concert with other studies in complementary disease models along with human autopsies, raise the possibility that neuronal infection may contribute to severe COVID-19 [ 58 ]. Brain and neuronal infection, as well as acute neurologic symptoms, have been documented in COVID-19 patients and human brain organoids [ 67 – 71 ], but this is an inconsistent finding [ 52 , 72 ]. Thus, the neuronal tropism of SARS-CoV-2 and its contribution to COVID-19 pathology remains controversial.…”

Section: Discussionmentioning

confidence: 99%

Cell-autonomous requirement for ACE2 across organs in lethal mouse SARS-CoV-2 infection

et al. 2023

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Angiotensin-converting enzyme 2 (ACE2) is the cell-surface receptor for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). While its central role in Coronavirus Disease 2019 (COVID-19) pathogenesis is indisputable, there remains significant debate regarding the role of this transmembrane carboxypeptidase in the disease course. These include the role of soluble versus membrane-bound ACE2, as well as ACE2-independent mechanisms that may contribute to viral spread. Testing these roles requires in vivo models. Here, we report humanized ACE2-floxed mice in which hACE2 is expressed from the mouse Ace2 locus in a manner that confers lethal disease and permits cell-specific, Cre-mediated loss of function, and LSL-hACE2 mice in which hACE2 is expressed from the Rosa26 locus enabling cell-specific, Cre-mediated gain of function. Following exposure to SARS-CoV-2, hACE2-floxed mice experienced lethal cachexia, pulmonary infiltrates, intravascular thrombosis and hypoxemia—hallmarks of severe COVID-19. Cre-mediated loss and gain of hACE2 demonstrate that neuronal infection confers lethal cachexia, hypoxemia, and respiratory failure in the absence of lung epithelial infection. In this series of genetic experiments, we demonstrate that ACE2 is absolutely and cell-autonomously required for SARS-CoV-2 infection in the olfactory epithelium, brain, and lung across diverse cell types. Therapies inhibiting or blocking ACE2 at these different sites are likely to be an effective strategy towards preventing severe COVID-19.

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Section: Discussionmentioning

confidence: 99%

Cell-autonomous requirement for ACE2 across organs in lethal mouse SARS-CoV-2 infection

et al. 2023

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“…Cellular self-organization during organoid differentiation allows the generation of complex brain anatomic regions resembling the dorsal cortex, ventral forebrain, retina, hippocampus, hypothalamus, choroid plexus, and midbrain–hindbrain boundary. These iPSC-derived brain organoids have been used to model various neurological pathologies, such as the toxicity effects of the Zika virus [ 68 , 70 ], sporadic Alzheimer’s disease [ 71 ], neurodevelopmental disease [ 72 , 73 , 74 ], microglia-mediated neuroinflammation [ 75 ], and (most recently) the neurotoxic effects of SARS-CoV-2 [ 76 , 77 , 78 , 79 ]. The generation of region-specific iPSC-derived brain organoids that closely parallel the neural epithelium has allowed researchers to investigate the mechanisms of SARS-CoV-2 disrupting the hematoencephalic barrier and infecting the cells of the central nervous system (CNS) [ 80 ].…”

Section: Ipsc-derived Organoids In Covid-19 Modelingmentioning

confidence: 99%

Induced Pluripotent Stem Cell-Derived Organoids: Their Implication in COVID-19 Modeling

Csöbönyeiová

Klein

Kuniaková

et al. 2023

IJMS

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The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a significant global health issue. This novel virus’s high morbidity and mortality rates have prompted the scientific community to quickly find the best COVID-19 model to investigate all pathological processes underlining its activity and, more importantly, search for optimal drug therapy with minimal toxicity risk. The gold standard in disease modeling involves animal and monolayer culture models; however, these models do not fully reflect the response to human tissues affected by the virus. However, more physiological 3D in vitro culture models, such as spheroids and organoids derived from induced pluripotent stem cells (iPSCs), could serve as promising alternatives. Different iPSC-derived organoids, such as lung, cardiac, brain, intestinal, kidney, liver, nasal, retinal, skin, and pancreatic organoids, have already shown immense potential in COVID-19 modeling. In the present comprehensive review article, we summarize the current knowledge on COVID-19 modeling and drug screening using selected iPSC-derived 3D culture models, including lung, brain, intestinal, cardiac, blood vessels, liver, kidney, and inner ear organoids. Undoubtedly, according to reviewed studies, organoids are the state-of-the-art approach to COVID-19 modeling.

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“…Establishing lower pathogenicity of new variants in humans populations is complicated by the rising levels of protective immunity due to vaccinations and/or past infections 66,70 . In vitro organoid systems provide another method for evaluating pathogenicity, with infection of neurons in brain organoids well described 37,71,72 , and BA.2 showing enhanced replication 73 . Infection of neurons results in their demise 71,72 , with type I IFN induction seen in some studies 72,73 but not others 37 .…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…In vitro organoid systems provide another method for evaluating pathogenicity, with infection of neurons in brain organoids well described 37,71,72 , and BA.2 showing enhanced replication 73 . Infection of neurons results in their demise 71,72 , with type I IFN induction seen in some studies 72,73 but not others 37 . Evasion of anti-spike antibodies is likely the main driver of SARS-CoV-2 evolution, as the majority of amino acid substitutions in new variants are in the spike protein 74,75 .…”

Section: Introductionmentioning

confidence: 99%

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Increased neurovirulence of omicron BA.5 and XBB variants over BA.1 in K18-hACE2 mice and human brain organoids

Stewart

Ellis

Yan

et al. 2022

Preprint

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A frequently repeated premise is that viruses evolve to become less pathogenic. This appears also to be true for SARS-CoV-2, although the increased level of immunity in human populations makes it difficult to distinguish between reduced intrinsic pathogenicity and increasing protective immunity. The reduced pathogenicity of the omicron BA.1 sub-lineage compared to earlier variants is well described and appears to be due to reduced utilization of TMPRRS2. That this reduced pathogenicity remains true for omicron BA.5 was recently reported. In sharp contrast, we show that a BA.5 isolate was significantly more pathogenic in K18-hACE2 mice than a BA.1 isolate, with BA.5 infection showing increased neurovirulence, encephalitis and mortality, similar to that seen for an original strain isolate. BA.5 also infected human cortical brain organoids to a greater extent than a BA.1 and original strain isolate. Neurons were the target of infection, with increasing evidence of neuron infection in COVID-19 patients. These results argue that while omicron virus may be associated with reduced respiratory symptoms, BA.5 shows increased neurovirulence compared to earlier omicron sub-variants.

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SARS-CoV-2 infects human brain organoids causing cell death and loss of synapses that can be rescued by treatment with Sofosbuvir

Cited by 36 publications

References 90 publications

Cell-autonomous requirement for ACE2 across organs in lethal mouse SARS-CoV-2 infection

Cell-autonomous requirement for ACE2 across organs in lethal mouse SARS-CoV-2 infection

Induced Pluripotent Stem Cell-Derived Organoids: Their Implication in COVID-19 Modeling

Increased neurovirulence of omicron BA.5 and XBB variants over BA.1 in K18-hACE2 mice and human brain organoids

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