Biology subjects

Cantuti-Castelvetri, L.

Publications and source records attributed to Cantuti-Castelvetri, L..

3 recordsLinked to original sources

bioRxiv2022

Spatial Transcriptomics-correlated Electron Microscopy

Current spatial transcriptomics methods identify cell states in a spatial context but lack morphological information. Scanning electron microscopy, in contrast, provides structural details at nanometer resolution but lacks molecular decoding of the diverse cellular states. To address this, we correlated MERFISH spatial transcriptomics with large area volume electron microscopy using adjacent tissue sections. We applied our technology to characterize the damage-associated microglial identities in mouse brain, allowing us, for the first time, to link the morphology of foamy microglia and interferon-response microglia with their transcriptional signatures.

neuroscience↗

bioRxiv2020

Neuropilin-1 facilitates SARS-CoV-2 cell entry and provides a possible pathway into the central nervous system

The causative agent of the current pandemic and coronavirus disease 2019 (COVID-19) is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)1. Understanding how SARS-CoV-2 enters and spreads within human organs is crucial for developing strategies to prevent viral dissemination. For many viruses, tissue tropism is determined by the availability of virus receptors on the surface of host cells2. Both SARS-CoV and SARS-CoV-2 use angiotensin-converting enzyme 2 (ACE2) as a host receptor, yet, their tropisms differ3-5. Here, we found that the cellular receptor neuropilin-1 (NRP1), known to bind furin-cleaved substrates, significantly potentiates SARS-CoV-2 infectivity, which was inhibited by a monoclonal blocking antibody against the extracellular b1b2 domain of NRP1. NRP1 is abundantly expressed in the respiratory and olfactory epithelium, with highest expression in endothelial cells and in the epithelial cells facing the nasal cavity. Neuropathological analysis of human COVID-19 autopsies revealed SARS-CoV-2 infected NRP1-positive cells in the olfactory epithelium and bulb. In the olfactory bulb infection was detected particularly within NRP1-positive endothelial cells of small capillaries and medium-sized vessels. Studies in mice demonstrated, after intranasal application, NRP1-mediated transport of virus-sized particles into the central nervous system. Thus, NRP1 could explain the enhanced tropism and spreading of SARS-CoV-2.

microbiology↗

bioRxiv2019

Loss of NPC1 enhances phagocytic uptake and impairs lipid trafficking in microglia

Niemann-Pick type C disease is a rare neurodegenerative disorder mainly caused by mutations in Npc1, resulting in abnormal late endosomal/lysosomal lipid storage. Although microgliosis is a prominent pathological feature, consequences of NPC1 loss on microglial function remain uncharacterized. Here, we provide an in-depth characterization of microglial proteomic signatures and phenotypes in a NPC1-deficient (Npc1-/-) murine model and patient blood-derived macrophages. We demonstrate enhanced phagocytic uptake and impaired lipid trafficking in Npc1-/- microglia that precede neuronal death. Loss of NPC1 compromises microglial developmental functions as revealed by increased synaptic pruning and deficient myelin turnover. Undigested myelin accumulates within multi-vesicular bodies of Npc1-/- microglia while lysosomal degradation remains preserved. To translate our findings to human disease, we generated novel ex vivo assays using patient macrophages that displayed similar proteomic disease signatures and lipid trafficking defects as murine Npc1-/- microglia. Thus, peripheral macrophages provide a novel promising clinical tool for monitoring disease progression and therapeutic efficacy in NPC patients. Our study underscores an essential role for NPC1 in immune cells and implies microglial therapeutic potential.

neuroscience↗