Biology subjects

de Witte, P.

Publications and source records attributed to de Witte, P..

3 recordsLinked to original sources

bioRxiv2022

The dissemination of Rift Valley fever virus to the eye and sensory neurons of zebrafish larvae is stat1 dependent.

The Rift Valley fever virus (RVFV) is listed by the WHO as priority disease and causes haemorrhagic fever, encephalitis, and permanent blindness. To study RVFV pathogenesis and identify small-molecule antivirals, we established a novel in vivo model using zebrafish larvae. Pericardial injection of RVFV resulted in ~4 log10 viral RNA copies/larva, which was inhibited by antiviral 2'-fluoro-2'-deoxycytidine. The optical transparency of the larvae allowed detection of RVFVeGFP in the liver and sensory nervous system, including the optic tectum and retina, but not the brain or spinal cord. Thus, RVFV-induced blindness likely occurs due to direct damage to the eye and peripheral neurons, rather than the brain. Treatment with JAK-inhibitor ruxolitinib, as well as knockout of stat1a but not stat1b, enhanced RVFV replication to ~6 log10 viral RNA copies/larva and ultra-bright livers, although without dissemination to sensory neurons or the eye, hereby confirming the critical role of stat1 in RVFV pathogenesis.

microbiology↗

bioRxiv2020

G3BP1 tethers the TSC complex to lysosomes and suppresses mTORC1 in the absence of stress granules

G3BP1 (Ras GTPase-activating protein-binding protein 1) is widely recognized as a core component of stress granules (SG), non-membranous RNA-protein-assemblies required for cellular survival under stress. We report that in the absence of SG, G3BP1 acts as lysosomal anchor of the Tuberous Sclerosis Complex (TSC) protein complex. By tethering the TSC complex to lysosomes, G3BP1 suppresses signaling through the metabolic master regulator mTORC1 (mechanistic target of rapamycin complex 1). Like the known TSC complex subunits, G3BP1 suppresses phenotypes related to mTORC1 hyperactivity in the context of tumors and neuronal dysfunction. Thus, G3BP1 is not only a core component of SG but also a key element of lysosomal TSC-mTORC1 signaling. HighlightsThe bona fide stress granule component G3BP1 O_LIis a key element of the TSC-mTORC1 signaling axis. C_LIO_LItethers the TSC complex to lysosomes. C_LIO_LIprevents mTORC1 hyperactivation by metabolic stimuli. C_LIO_LIsuppresses mTORC1-driven cancer cell motility and epileptiform activity. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/044081v3_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@77cb4forg.highwire.dtl.DTLVardef@c4d1a0org.highwire.dtl.DTLVardef@19e83acorg.highwire.dtl.DTLVardef@1d6a378_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2019

A robust human norovirus replication model in zebrafish larvae

Human noroviruses (HuNoVs) are an important cause of epidemic and endemic acute gastroenteritis worldwide; annually about 700 million people develop a HuNoV infection resulting in [~]219,000 deaths and a societal cost estimated at 60 billion US dollars 1. The lack of robust small animal models has significantly hindered the understanding of norovirus biology and the development of effective therapeutics against HuNoV. Here we report that HuNoV GI and GII replicate to high titers in zebrafish (Danio rerio) larvae; replication peaks at day 2 post infection and is detectable for at least 6 days. HuNoV is detected in cells of the hematopoietic lineage, the intestine, liver and pancreas. Antiviral treatment reduces HuNoV replication by >2 log10, showing that this model is suited for antiviral studies. Downregulation of fucosyltransferase 8 (fut8) in the larvae reduces HuNoV replication, highlighting a common feature with infection in humans. Zebrafish larvae constitute a simple and robust replication model that will largely facilitate studies of HuNoV biology and the development of antiviral strategies.

microbiology↗