Inhibition of hostN-myristoylation compromises the infectivity of SARS-CoV-2 due to Golgi-bypassing egress from lysosomes and endoplasmic reticulum DOI Creative Commons

Saber H. Saber,

Mohammed R. Shaker,

Julian Sng

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: March 3, 2023

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which caused the disease 2019 (COVID-19) pandemic, remains a global health concern despite vaccines, neutralizing antibodies, and antiviral drugs. Emerging mutations can reduce effectiveness of these treatments, suggesting that targeting host cell factors may be valuable alternative. N -myristoyltransferases (NMT) are essential enzymes for protein -myristoylation, affecting stability, interaction, localization, function numerous proteins. We demonstrate selective inhibition NMT decreases SARS-CoV-2 infection by 90% in human lung primary nasal epithelial cells, choroid plexus-cortical neuron organoids. does not affect viral entry, replication or release, but impairs maturation incorporation envelope proteins into newly assembled virions, leading to compromised infectivity released virions. The triggers Golgi-bypassing pathway progeny virion egress, occurs through endoplasmic reticulum lysosomal intermediates.

Language: Английский

SARS-CoV-2 infects epithelial cells of the blood-cerebrospinal fluid barrier rather than endothelial cells or pericytes of the blood-brain barrier DOI Creative Commons
Chiara Stüdle, Hideaki Nishihara, Sven Wischnewski

et al.

Fluids and Barriers of the CNS, Journal Year: 2023, Volume and Issue: 20(1)

Published: Oct. 24, 2023

As a consequence of SARS-CoV-2 infection various neurocognitive and neuropsychiatric symptoms can appear, which may persist for several months post infection. However, cell type-specific routes brain underlying mechanisms resulting in neuroglial dysfunction are not well understood.

Language: Английский

Citations

14
Protocol for generating embedding-free brain organoids enriched with oligodendrocytes DOI Creative Commons
Bahaa H. Almhanawi,

Marta Boira Marti,

Sean D. Morrison

et al.

STAR Protocols, Journal Year: 2023, Volume and Issue: 4(4), P. 102725 - 102725

Published: Nov. 16, 2023

In response to the scarcity of advanced in vitro models dedicated human CNS white matter research, we present a protocol generate neuroectoderm-derived embedding-free brain organoids enriched with oligodendrocytes. We describe steps for neuroectoderm differentiation, development neural spheroids, and their transferal Matrigel. then detail procedures development, maturation, application oligodendrocyte-enriched organoids. The presence myelin-producing cells makes these useful studying diseases, such as leukodystrophy.

Language: Английский

Citations

7
A developmental cell atlas of the human thyroid gland DOI Creative Commons
Hassan Massalha, Mi K. Trinh, Erick Armingol

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 22, 2024

The primary function of the thyroid gland is synthesis and release hormones, which are essential for health from embryogenesis to adulthood. Thyroid disorders occur frequently include congenital hypothyroidism, occurs due aberrant development (thyroid dysgenesis) or impaired hormone particularly prevalent in trisomy 21 (T21). In contrast, carcinoma, an acquired disorder, most common endocrine malignancy both paediatric adult populations. Understanding molecular basis dysgenesis carcinoma remains challenging, requires improved understanding foetal development. To address this, we generated a comprehensive spatiotemporal atlas human during first second trimesters pregnancy. Profiling over 200,000 cells with single-cell sequencing revealed key cell types involved development, including hormone-producing thyrocytes. We discovered that follicular heterogeneous epithelial populations consisting two main functional subtypes (fTFC1, fTFC2), fTFC2 expressing increased levels PAX8, spatial transcriptomics subtype co-occurrence within individual follicles. While fTFC1 persist thyroid, minor population amongst additional PAX8-positive subsets. observed T21 age-matched specimens, thyrocytes showed transcriptional signatures cytoskeletal disorganisation altered interactions extracellular matrix, as well compensatory activation metabolic stress gene programs upregulation biosynthetic genes. line proportions healthy papillary cancer children transcriptionally enriched signature compared adults. All together, these findings reveal thyrocyte heterogeneity across lifespan provide insights into disease, informing potential therapeutic interventions.

Language: Английский

Citations

0
SARS-CoV-2 infection in hiPSC-derived neurons is cathepsin-dependent and causes accumulation of HIF1alpha and phosphorylated tau DOI Creative Commons
Pinja Kettunen, Janika Ruuska, Tania Quirin

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 23, 2024

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been shown to infect the human brain and a subset of neurons in vitro. We have previously demonstrated that virus enters induced pluripotent stem cell (hiPSC)-derived via an endosomal-lysosomal pathway, which is dependent on low levels angiotensin-converting enzyme (ACE2) independent transmembrane serine protease (TMPRSS2). Here, we use hiPSC-derived overexpressing ACE2 co-culture with astrocytes show infection both SARS-CoV-2 Wuhan Omicron XBB.1.5 variants cathepsins can be efficiently blocked by inhibitor cathepsin B (CA-074-ME). result was reproducible non-transgenic cortical organoids. L SB412515 less effective against strain but equally variant. Using PCR reinfection assays, replicate 2D co-cultures. Interestingly, infectivity newly produced virions declined at 24 hours post-infection despite further increase released viral RNA later time points, suggesting possible activation antiviral response and/or astrocytes, supported correspondent secreted cytokines. Furthermore, number infected decreased within five days, eventually leads death target neuronal also caused accumulation hypoxia-inducible stress factor HIF1-alpha under normoxia. Finally, confirm expand previous finding neurons, microtubule-associated protein tau hyperphosphorylated multiple loci, including S202/T205, mislocalized soma neurons. Hyperphosphorylation mislocalization are hallmarks Alzheimer's disease (AD) other tauopathies. Our data provides evidence supporting neurodegenerative potential infection.

Language: Английский

Citations

0
Inhibition of hostN-myristoylation compromises the infectivity of SARS-CoV-2 due to Golgi-bypassing egress from lysosomes and endoplasmic reticulum DOI Creative Commons

Saber H. Saber,

Mohammed R. Shaker,

Julian Sng

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: March 3, 2023

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which caused the disease 2019 (COVID-19) pandemic, remains a global health concern despite vaccines, neutralizing antibodies, and antiviral drugs. Emerging mutations can reduce effectiveness of these treatments, suggesting that targeting host cell factors may be valuable alternative. N -myristoyltransferases (NMT) are essential enzymes for protein -myristoylation, affecting stability, interaction, localization, function numerous proteins. We demonstrate selective inhibition NMT decreases SARS-CoV-2 infection by 90% in human lung primary nasal epithelial cells, choroid plexus-cortical neuron organoids. does not affect viral entry, replication or release, but impairs maturation incorporation envelope proteins into newly assembled virions, leading to compromised infectivity released virions. The triggers Golgi-bypassing pathway progeny virion egress, occurs through endoplasmic reticulum lysosomal intermediates.

Language: Английский

Citations

0