Biology subjects

Huertas, M.

Publications and source records attributed to Huertas, M..

4 recordsLinked to original sources

bioRxiv2020

A zebrafish model for COVID-19 recapitulates olfactory and cardiovascular pathophysiologies caused by SARS-CoV-2

The COVID-19 pandemic has prompted the search for animal models that recapitulate the pathophysiology observed in humans infected with SARS-CoV-2 and allow rapid and high throughput testing of drugs and vaccines. Exposure of larvae to SARS-CoV-2 Spike (S) receptor binding domain (RBD) recombinant protein was sufficient to elevate larval heart rate and treatment with captopril, an ACE inhibitor, reverted this effect. Intranasal administration of SARS-CoV-2 S RBD in adult zebrafish recombinant protein caused severe olfactory and mild renal histopathology. Zebrafish intranasally treated with SARS-CoV-2 S RBD became hyposmic within minutes and completely anosmic by 1 day to a broad-spectrum of odorants including bile acids and food. Single cell RNA-Seq of the adult zebrafish olfactory organ indicated widespread loss of expression of olfactory receptors as well as inflammatory responses in sustentacular, endothelial, and myeloid cell clusters. Exposure of wildtype zebrafish larvae to SARS-CoV-2 in water did not support active viral replication but caused a sustained inhibition of ace2 expression, triggered type 1 cytokine responses and inhibited type 2 cytokine responses. Combined, our results establish adult and larval zebrafish as useful models to investigate pathophysiological effects of SARS-CoV-2 and perform pre-clinical drug testing and validation in an inexpensive, high throughput vertebrate model.

immunology↗

bioRxiv2019

Conditions for synaptic specificity during the maintenance phase of synaptic plasticity

Activity-dependent modifications of synaptic efficacies are a cellular substrate of learning and memory. Experimental evidence shows that these modifications are synapse-specific and that the long-lasting effects are associated with the sustained increase in concentration of specific proteins like PKM{zeta}. However, such proteins are likely to diffuse away from their initial synaptic location and spread out to neighboring synapses, potentially compromising synapse-specificity. In this paper we address the issue of synapse-specificity during memory maintenance. Assuming that the long-term maintenance of synaptic plasticity is accomplished by a molecular switch we perform simulations using the reaction-diffusion package in NEURON and analytical calculations to determine the limits of synaptic-specificity during maintenance. Moreover, we explore the effects of the diffusion and degradation rates of proteins and of the geometrical characteristics of dendritic spines on synapse specificty. We conclude that the necessary conditions for synaptic specificity during maintenance require that protein synthesis occurs in dendritic spines and that the activated dendritic spines exhibit small neck diameters.

neuroscience↗

bioRxiv2018

Olfactory sensory neurons mediate ultra-rapid antiviral immune responses in teleosts in a TrkA-dependent manner

The nervous system is known to regulate host immune responses. However, the ability of neurons to detect danger and initiate immune responses at barrier tissues is unclear. Vertebrate olfactory sensory neurons (OSNs) are located in direct contact with the external environment and therefore directly exposed to pathogens. Here, we report that nasal delivery of rhadboviruses induced apoptosis in crypt OSNs in rainbow trout olfactory organ (OO) via the interaction of the OSN TrkA receptor with viral glycoprotein. This signal resulted in pro-inflammatory responses in the OO and dampened inflammation in the olfactory bulb (OB). CD8+ cells infiltrated the OO within minutes of nasal viral delivery and this response was abrogated when TrkA was blocked. Infiltrating CD8+ cells originated from the microvasculature surrounding the OB and not the periphery. Ablation of crypt neurons in zebrafish resulted in increased susceptibility to rhabdoviral challenge. Our results, therefore, indicate a novel function for OSNs as a first layer of pathogen detection in vertebrates.

immunology↗

bioRxiv2018

Enabling the hypothesis-driven prioritization of ligand candidates in big databases: Screenlamp and its application to GPCR inhibitor discovery for invasive species control

While the advantage of screening vast databases of molecules to cover greater molecular diversity is often mentioned, in reality, only a few studies have been published demonstrating inhibitor discovery by screening more than a million compounds for features that mimic a known three-dimensional ligand. Two factors contribute: the general difficulty of discovering potent inhibitors, and the lack of free, user-friendly software to incorporate project-specific knowledge and user hypotheses into 3D ligand-based screening. The Screenlamp modular toolkit presented here was developed with these needs in mind. We show Screenlamps ability to screen more than 12 million commercially available molecules and identify potent in vivo inhibitors of a G protein-coupled bile acid receptor within the first year of a discovery project. This pheromone receptor governs sea lamprey reproductive behavior, and to our knowledge, this project is the first to establish the efficacy of computational screening in discovering lead compounds for aquatic invasive species control. Significant enhancement in activity came from selecting compounds based on one of the hypotheses: that matching two distal oxygen groups in the three-dimensional structure of the pheromone is crucial for activity. Six of the 15 most active compounds met these criteria. A second hypothesis - that presence of an alkyl sulfate side chain results in high activity - identified another 6 compounds in the top 10, demonstrating the significant benefits of hypothesis-driven screening.

bioinformatics↗