Biology subjects

Di Nardo, A.

Publications and source records attributed to Di Nardo, A..

4 recordsLinked to original sources

bioRxiv2024

Characterising alphacoronavirus phenotypic traits through diversity-driven selection of spike

The capacity for viruses to spillover from one host to another is dependent on their ability to bind to and enter cells from a new host. Using a computational approach that maximises phylogenetic diversity, we selected an optimal subset of 40 alphacoronavirus spike proteins, including the two human viruses NL63 and 229E, and characterised their host-range using broad mammalian APN and ACE2 receptor libraries. Based on this data, we were able to determine molecular genotypes that contribute to receptor tropism and identify alphacoronaviruses with broad (generalist) or restricted (specialist) receptor usage. Strikingly, we observed that generalism and specialism can vary significantly between closely related viruses. Using structural information, we identified key residues that determine the bat tropism of 229E-like viruses, as well as residues in the ACE2 receptor that likely restrict NL63 infection of certain mammals. Furthermore, we observed that the host range of certain bat alphacoronaviruses is expanded by TMPRSS2 priming of spike. All APN- and ACE2-using alphaCoVs in our study interacted with the receptor of at least one animal species within ecological proximity to humans, suggesting new routes for spillover. However, most bat alphacoronaviruses did not use any of receptors in our screen, refining our understanding of coronavirus entry. We propose a new approach to investigating receptor usage for viral orders/families/genera, which is not constrained by focused analysis of a limited number of sequences from human-tropic viruses. Understanding phenotypic traits, such as entry, at this genus-wide level can revolutionise our ability to predict zoonotic potential.

microbiology↗

bioRxiv2020

OTX2 non-cell autonomous activity regulates inner retinal function

OTX2 is a homeoprotein transcription factor expressed in photoreceptors and bipolar cells in the retina. OTX2, like many other homeoproteins, transfers between cells and exerts non-cell autonomous effects such as promoting survival of retinal ganglion cells that do not express the protein. Here we used a genetic approach to target extracellular OTX2 in the retina by conditional expression of a secreted single chain anti-OTX2 antibody. Compared to control mice, the expression of this antibody by Parvalbumin-expressing neurons in the retina is followed by a reduction in visual acuity in one-month-old mice with no alteration of the retinal structure or cell type number or aspect. A- and b-waves measured by electroretinogram were also indistinguishable from control mice, suggesting no functional deficit of photoreceptors and bipolar cells. Mice expressing the OTX2-neutralizing antibody did show a significant doubling in the flicker amplitude, consistent with a change in inner retinal function. Our results show that interfering in vivo with OTX2 non-cell autonomous activity in the postnatal retina leads to an alteration in inner retinal cell functions and causes a deficit in visual acuity. Significance statementOTX2 is a homeoprotein transcription factor expressed in retinal photoreceptors and bipolar cells. Although the Otx2 locus is silent in the inner retina, the protein is detected in cells of the ganglion cell layer consistent with the ability of this class of proteins to transfer between cells. We expressed a secreted single chain antibody (scFv) against OTX2 in the retina to neutralize extracellular OTX2. Antibody expression leads to reduced visual acuity with no change in retinal structure, or photoreceptor or bipolar physiology; however, activity in the inner retina was altered. Thus, interfering with OTX2 non-cell autonomous activity in postnatal retina alters inner retinal function and causes vision loss, highlighting the physiological value of homeoprotein direct non-cell autonomous signaling.

neuroscience↗

bioRxiv2020

Comparing Phylogeographies: Incompatible Geographical Histories in Pathogens' Genomes

Modern phylogeography aims at reconstructing the geographic diffusion of organisms based on their genomic sequences and spatial information. Phylogeographic approaches usually ignore the possibility of recombination, which decouples the evolutionary and geographic histories of different parts of the genome. Genomic regions of recombining or reassorting pathogens often originate and evolve at different times and locations, which characterised their unique spatial histories. Measuring the extent of these differences requires new methods to compare geographic information on phylogenetic trees reconstructed from different parts of the genome. Here we develop for the first time a set of measures of phylogeographic incompatibility aimed at detecting differences between geographical histories in terms of distances between phylogeographies. We study the effect of varying demography and recombination on phylogeographic incompatibilities using coalescent simulations. We further apply these measures to the evolutionary history of human and livestock pathogens, either reassorting or recombining, such as the Victoria and Yamagata lineages of influenza B and the O/Ind-2001 foot-and-mouth disease virus strain. Our results reveal diverse geographical paths of diffusion that characterise the origins and evolutionary histories of different viral genes and genomic segments. phylogeography, recombination, viral evolution

genomics↗

bioRxiv2018

Extracellular Pax6 regulates tangential Cajal-Retzius cell migration

The embryonic mouse cortex displays a striking low caudo-medial and high rostro-lateral graded expression of the homeoprotein transcription factor Pax6, which presents both cell autonomous and direct non-cell autonomous activities. Through the genetic induction of anti-Pax6 single-chain antibody secretion, we have analyzed Pax6 non-cell autonomous activity on the migration of cortical hem- and septum-derived Cajal-Retzius (CR) neurons by live imaging of flat mount developing cerebral cortices. We observed that blocking extracellular Pax6 disrupts tangential CR cell migration patterns. We found a decrease in the distance travelled and changes both in directionality and in the depth at which CR cells migrate. Tracking of single CR cells in mutant cortices revealed that extracellular Pax6 neutralization enhances or reduces contact repulsion in medial and lateral regions, respectively. This study demonstrates that secreted Pax6 controls neuronal migration thus acting as a bona fide morphogen at an early stage of cerebral cortex development.\n\nSummary statementCajal-Retzius cell distribution in the embryonic cortex participates in determining the size and positioning of cortical areas. Here, Kaddour et al. establish that the direct non-cell autonomous activity of the Pax6 transcription factor regulates Cajal-Retzius cell migration.

neuroscience↗