Neuroinvasion and anosmia are independent phenomena upon infection with SARS-CoV-2 and its variants

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Июль 26, 2023

Abstract Anosmia was identified as a hallmark of COVID-19 early in the pandemic, however, with emergence variants concern, clinical profile induced by SARS-CoV-2 infection has changed, anosmia being less frequent. Here, we assessed clinical, olfactory and neuroinflammatory conditions golden hamsters infected original Wuhan strain, its isogenic ORF7-deletion mutant three variants: Gamma, Delta, Omicron/BA.1. We show that animals develop variant-dependent disease including anosmia, ORF7 contributes to induction dysfunction. Conversely, all are neuroinvasive, regardless presentation they induce. Taken together, this confirms neuroinvasion independent phenomena upon infection. Using newly generated nanoluciferase-expressing SARS-CoV-2, validate pathway major entry point into brain vivo demonstrate vitro travels retrogradely anterogradely along axons microfluidic neuron-epithelial networks.

Язык: Английский

---

SARS-CoV-2 and the spike protein in endotheliopathy

Trends in Microbiology, Год журнала: 2023, Номер 32(1), С. 53 - 67

Опубликована: Июнь 12, 2023

Язык: Английский

---

Differential effects of SARS-CoV-2 variants on central nervous system cells and blood–brain barrier functions

Journal of Neuroinflammation, Год журнала: 2023, Номер 20(1)

Опубликована: Авг. 3, 2023

Although mainly causing a respiratory syndrome, numerous neurological symptoms have been identified following of SARS-CoV-2 infection. However, how the virus affects brain and mutations carried by different variants modulate those remain unclear.We used primary human pericytes, foetal astrocytes, endothelial cells microglial cell line to investigate effect several concern or interest on their functional activities. Cells 3D blood-brain barrier model were infected with wild-type form SARS-CoV-2, Alpha, Beta, Delta, Eta, Omicron (BA.1) at various MOI. supernatant evaluate susceptibility using microscopic assay as well effects infection (i) metabolic activity colorimetric MTS assay; (ii) viral cytopathogenicity xCELLigence system; (iii) extracellular glutamate concentration fluorometric (iv) modulation permeability.We demonstrate that productive is variant dependent all induce stress CNS cells. The was cytopathic types except whilst Alpha Beta only for pericytes. Lastly increases permeability variants, concentration, which can lead excitotoxicity altered neurotransmission.These results suggest neurotropic, deleterious consequences integrity central nervous system cells, could underlie disorders

Язык: Английский

---

SARS-CoV-2 omicron BA.5 and XBB variants have increased neurotropic potential over BA.1 in K18-hACE2 mice and human brain organoids

Frontiers in Microbiology, Год журнала: 2023, Номер 14

Опубликована: Ноя. 23, 2023

The reduced pathogenicity of the omicron BA.1 sub-lineage compared to earlier variants is well described, although whether such attenuation retained for later like BA.5 and XBB remains controversial. We show that isolates were significantly more pathogenic in K18-hACE2 mice than a isolate, showing increased neurotropic potential, resulting fulminant brain infection mortality, similar seen original ancestral isolates. also infected human cortical organoids greater extent In brains mice, neurons main target infection, neuronal progenitor cells immature infected. results herein suggest evolving may have increasing potential.

Язык: Английский

---

New insights into neuropathology and pathogenesis of autoimmune glial fibrillary acidic protein meningoencephalomyelitis

Acta Neuropathologica, Год журнала: 2024, Номер 147(1)

Опубликована: Фев. 3, 2024

Abstract Anti-glial fibrillary acidic protein (GFAP) meningoencephalomyelitis (autoimmune GFAP astrocytopathy) is a new autoimmune central nervous system (CNS) disease diagnosable by the presence of anti-GFAP autoantibodies in cerebrospinal fluid and presents as majority patients. Only few neuropathological reports are available little known about pathogenic mechanisms. We performed histopathological study two autopsies nine CNS biopsies patients with found predominantly lymphocytic one autopsy case granulomatous inflammatory phenotype. Inflammatory infiltrates were composed B T cells, including tissue-resident memory cells. Although obvious astrocytic damage was absent GFAP-staining, we cytotoxic cell-mediated reactions reflected CD8 + /perforin /granzyme A/B polarized towards astrocytes. MHC-class-I upregulated reactive astrocytes all but not healthy controls. Importantly, observed prominent immunoreactivity complement factor C4d. Finally, provided insight into an early phase autoimmunity pug dog encephalitis that characterized marked meningoencephalitis selective loss AQP4 lesions. Our findings indicate immune reaction present autoimmunity. Complement C4d deposition on could either represent cause or consequence reactivity. Selective canine case, mild subacute chronic stages human disease, probably due to high regeneration potential The phenotypes might reflect different lesion development patient-specific modifications response. Future studies will be necessary investigate possible implications pathological subtypes for clinical course therapeutic strategies.

Язык: Английский

---

Neuroinflammation generated by HIV-infected microglia promotes dysfunction and death of neurons in human brain organoids

PNAS Nexus, Год журнала: 2024, Номер 3(5)

Опубликована: Апрель 29, 2024

Abstract Despite the success of combination antiretroviral therapy (ART) for individuals living with HIV, mild forms HIV-associated neurocognitive disorder (HAND) continue to occur. Brain microglia form principal target HIV infection in brain. It remains unknown how these cells leads neuroinflammation, neuronal dysfunction, and/or death observed HAND. Utilizing two different inducible pluripotent stem cell-derived brain organoid models (cerebral and choroid plexus [ChP] organoids) containing microglia, we investigated pathogenic changes associated infection. Infection was a sharp increase CCL2 CXCL10 chemokine gene expression activation many type I interferon stimulated genes (MX1, ISG15, ISG20, IFI27, IFITM3 others). Production proinflammatory chemokines persisted at low levels after treatment cell cultures ART, consistent persistence HAND following clinical introduction ART. Expression multiple members S100 family inflammatory sharply increased measured by single-cell RNA-seq. However, not limited but also detected more broadly uninfected stromal cells, mature immature ChP neural progenitor importantly bystander neurons suggesting propagation response cells. Neurotransmitter transporter declined neurons, accompanied promoting cellular senescence death. Together, studies underscore an generated HIV-infected is propagated ultimately resulting dysfunction neurons.

Язык: Английский

---

Precision nutrition to reset virus-induced human metabolic reprogramming and dysregulation (HMRD) in long-COVID

npj Science of Food, Год журнала: 2024, Номер 8(1)

Опубликована: Март 30, 2024

Язык: Английский

---

NRP1 is a receptor for mammalian orthoreovirus engaged by distinct capsid subunits

Cell Host & Microbe, Год журнала: 2024, Номер 32(6), С. 980 - 995.e9

Опубликована: Май 9, 2024

Язык: Английский

---

Regulation of type I and type III interferon induction in response to pathogen sensing

Current Opinion in Immunology, Год журнала: 2024, Номер 87, С. 102424 - 102424

Опубликована: Апрель 1, 2024

Type I and III interferons (IFN-I IFN-III) have a central role in the early antimicrobial response against invading pathogens. Induction of IFN-Is IFN-IIIs arises due to sensing by pattern recognition receptors pathogen-associated molecular patterns (from micro-organisms) or damage-associated (DAMPs; produced host cells). Here, we review recent developments on how IFN-I IFN-III expression is stimulated different pathogens signalling pathways leading IFN induction are tightly regulated. We also summarise growing knowledge that lead severe acute respiratory syndrome coronavirus 2.

Язык: Английский

---

iPSC‐derived human cortical organoids display profound alterations of cellular homeostasis following SARS‐CoV‐2 infection and Spike protein exposure

The FASEB Journal, Год журнала: 2025, Номер 39(4)

Опубликована: Фев. 14, 2025

Abstract COVID‐19 commonly leads to respiratory issues, yet numerous patients also exhibit a diverse range of neurological conditions, suggesting detrimental impact SARS‐CoV‐2 or the viral Spike protein on central nervous system. Nonetheless, molecular pathway behind pathology and presumed neurotropism remains largely unexplored. We generated human cortical organoids (HCOs) derived from induced pluripotent stem cells (hiPSC) assess: (1) expression main entry factors; (2) their vulnerability infection; (3) infection exposure transcriptome. Results proved that HCOs express receptors co‐receptors; may be productively infected by SARS‐CoV‐2; particles released SARS‐CoV‐2‐infected are able re‐infect another cellular line; (4) resulted in activation apoptotic stress pathways, along with inflammatory processes. Notably, these effects were recapitulated when exposed alone. The data obtained demonstrate likely infects probably through binding ACE2, CD147, NRP1 factors. Furthermore, alone sufficient disrupt homeostasis induce neurotoxic effects, potentially contributing onset long‐COVID symptoms.

Язык: Английский

---