Biology subjects

Wilson, A.

Publications and source records attributed to Wilson, A..

At least 37 records · Page 2Linked to original sources

bioRxiv2024

Uukuniemi virus infection causes a pervasive remodelling of the RNA-binding proteome in tick cell cultures

Cellular RNA-binding proteins (RBPs) are pivotal for the viral lifecycle, mediating key host-virus interactions that promote or repress virus infection. While these interactions have been largely studied in the vertebrate host, no comprehensive analyses of protein-RNA interactions occurring in cells of arbovirus vectors, in particular ticks, have been performed to date. Here we systematically identified the responses of the RNA-binding proteome (RBPome) to infection with a prototype bunyavirus (Uukuniemi virus; UUKV) in tick cells and discovered changes in RNA-binding activity for 283 proteins. In an orthogonal approach, we analysed the composition of the viral ribonucleoprotein by immunoprecipitation of UUKV nucleocapsid protein (N) in infected cells. We found many tick RBPs that are regulated by UUKV infection and associate with viral nucleocapsid protein complexes. We confirmed experimentally that these RBPs impact UUKV infection. This includes the tick homolog of topoisomerase 3B (TOP3B), a protein able to manipulate the topology of RNA, which showed an effect on viral particle production. Our data thus reveals the first protein-RNA interaction map for infected tick cells. Research highlightsO_LIUUKV RNAs interact with nearly three hundred tick cell RBPs. C_LIO_LIDemonstrated an enrichment of N protein interactors within the upregulated RIC data suggesting a direct involvement in viral RNA metabolism and translation. C_LIO_LIDeveloped a robust methodology to silence gene expression in tick cell cultures. C_LIO_LIThe TOP3B complex facilitates efficient packaging of UUKV virions. C_LI

microbiology↗

bioRxiv2024

Pharmacological rescue of motor circuit dysfunction in a Drosophila model of paroxysmal dyskinesia

BackgroundParoxysmal dyskinesias (PxDs) are characterised by bouts of involuntary dystonic and choreiform movements. The patho-mechanisms underlying these debilitating disorders remain poorly understood, and drug treatments are often limited. We recently generated a Drosophila model of a PxD-linked mutation causing BK potassium channel gain- of-function (BK GOF), and showed that BK GOF perturbs movement in Drosophila by disrupting neurodevelopment. However, whether locomotor capacity in BK GOF flies can be pharmacologically restored following neurodevelopmental insults has remained unclear. ObjectiveTo identify pharmacological suppressors of motor defects caused by BK GOF. MethodsUsing adult BK GOF flies, we performed an unbiased, in vivo, locomotion-based screen of 370 FDA-approved drugs. To test the impact of positive hits from this screen on motor circuit activity, we used optical imaging to record the intrinsic rhythmic activity of Drosophila larval motor circuits driving peristalsis and turning behaviors. ResultsWe found that inhibitors of acetylcholinesterase - a protein that degrades acetylcholine in cholinergic synapses - partially rescued movement defects caused by BK GOF. Inhibition of acetylcholinesterase also partially restored intrinsic activity of motor circuits controlling forward movement and turning in BK GOF larvae. ConclusionsOur findings indicate that elevating cholinergic tone can reverse motor circuit dysfunction in an animal model of PxD caused by BK GOF. Furthermore, our study provides proof-of-principle that Drosophila can be utilised for screens to uncover putative drug treatments for involuntary movement disorders.

neuroscience↗

bioRxiv2024

Corticosteroids prevent pathological angiogenesis yet compromise reparative vascular remodeling in the retina

Tissue inflammation is often broadly associated with cellular damage, yet sterile inflammation also plays critical roles in beneficial tissue remodeling. In the central nervous system (CNS), this is observed through a predominantly innate immune response in retinal vascular diseases such as age-related macular degeneration, diabetic retinopathy and retinopathy of prematurity. Here we set out to elucidate the dynamics of the immune response during progression and regression of pathological neovascularization in retinopathy. In a mouse model of oxygen-induced retinopathy, we report that broad spectrum corticosteroid drugs such as dexamethasone suppress initial formation of pathological pre-retinal neovascularization in early stages of disease, yet blunt successive waves of reparative inflammation and hence prevent beneficial vascular remodeling. Using genetic depletion of distinct components of the innate immune response, we demonstrate that CX3C chemokine receptor 1 (CX3CR1)-expressing microglia contribute to angiogenesis. Conversely, myeloid cells expressing Lyz-M (lysozyme 2) are recruited to sites of damaged blood vessels and pathological neovascularization where they partake in a reparative process that ultimately restores circulatory homeostasis to the retina. Hence, the Janus-faced properties of anti-inflammatory drugs should be considered when treating retinal vascular disease and particularly in stages associated with persistent neovascularization.

immunology↗

bioRxiv2024

Targeting Fatty Acid Desaturase I Inhibits Renal Cancer Growth Via ATF3-mediated ER Stress Response

Monounsaturated fatty acids (MUFAs) play a pivotal role in maintaining endoplasmic reticulum (ER) homeostasis, an emerging hallmark of cancer. However, the role of polyunsaturated fatty acid (PUFAs) desaturation in persistent ER stress driven by oncogenic abnormalities remains elusive. Fatty Acid Desaturase 1 (FADS1) is a rate-limiting enzyme controlling the bioproduction of long-chain PUFAs. Our previous research has demonstrated the significant role of FADS1 in cancer survival, especially in kidney cancers. We explored the underlying mechanism in this study. We found that pharmacological inhibition or knockdown of the expression of FADS1 effectively inhibits renal cancer cell proliferation and induces cell cycle arrest. The stable knockdown of FADS1 also significantly inhibits tumor formation in vivo. Mechanistically, we show that while FADS1 inhibition induces ER stress, its expression is also augmented by ER-stress inducers. Notably, FADS1-inhibition sensitized cellular response to ER stress inducers, providing evidence of FADS1s role in modulating the ER stress response in cancer cells. We show that, while FADS1 inhibition-induced ER stress leads to activation of ATF3, ATF3-knockdown rescues the FADS1 inhibition-induced ER stress and cell growth suppression. In addition, FADS1 inhibition results in the impaired biosynthesis of nucleotides and decreases the level of UPD-N-Acetylglucosamine, a critical mediator of the unfolded protein response. Our findings suggest that PUFA desaturation is crucial for rescuing cancer cells from persistent ER stress, supporting FADS1 as a new therapeutic target.

cancer biology↗

bioRxiv2024

COVID-19 during pregnancy alters circulating extracellular vesicle cargo and their effects on trophoblast

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and resulting coronavirus disease (COVID-19) causes placental dysfunction, which increases the risk of adverse pregnancy outcomes. While abnormal placental pathology resulting from COVID-19 is common, direct infection of the placenta is rare. This suggests that pathophysiology associated with maternal COVID-19, rather than direct placental infection, is responsible for placental dysfunction and alteration of the placental transcriptome. We hypothesized that maternal circulating extracellular vesicles (EVs), altered by COVID-19 during pregnancy, contribute to placental dysfunction. To examine this hypothesis, we characterized maternal circulating EVs from pregnancies complicated by COVID-19 and tested their effects on trophoblast cell physiology in vitro. We found that the gestational timing of COVID-19 is a major determinant of circulating EV function and cargo. In vitro trophoblast exposure to EVs isolated from patients with an active infection at the time of delivery, but not EVs isolated from Controls, altered key trophoblast functions including hormone production and invasion. Thus, circulating EVs from participants with an active infection, both symptomatic and asymptomatic cases, can disrupt vital trophoblast functions. EV cargo differed between participants with COVID-19 and Controls, which may contribute to the disruption of the placental transcriptome and morphology. Our findings show that COVID-19 can have effects throughout pregnancy on circulating EVs and circulating EVs are likely to participate in placental dysfunction induced by COVID-19.

pathology↗

bioRxiv2023

Aging and intraocular pressure homeostasis in mice

Age and elevated intraocular pressure (IOP) are the two primary risk factors for glaucoma, an optic neuropathy that is the leading cause of irreversible blindness. In most people, IOP is tightly regulated over a lifetime by the conventional outflow tissues. However, the mechanistic contributions of age to conventional outflow dysregulation, elevated IOP and glaucoma are unknown. To address this gap in knowledge, we studied how age affects the morphology, biomechanical properties and function of conventional outflow tissues in C57BL/6 mice, which have an outflow system similar to humans. As reported in humans, we observed that IOP in mice was maintained within a tight range over their lifespan. Remarkably, despite a constellation of age-related changes to the conventional outflow tissues that would be expected to hinder aqueous drainage and impair homeostatic function (decreased cellularity, increased pigment accumulation, increased cellular senescence and increased stiffness), outflow facility, a measure of conventional outflow tissue fluid conductivity, was stable with age. We conclude that the murine conventional outflow system has significant functional reserve in healthy eyes. However, these age-related changes, when combined with other underlying factors, such as genetic susceptibility, are expected to increase risk for ocular hypertension and glaucoma.

physiology↗

bioRxiv2023

CREBBP lysine acetyltransferase domain mutations create zombie enzymes that alter chromatin loading dynamics and prevent EP300 redundancy

Epigenetic regulation of gene expression is fundamental to cell state transitions. A prominent example of this is the epigenetically-regulated generation of transitory cells states within the germinal center (GC) reaction that are required for humoral immunity. The deregulation of these processes through somatic mutations can give rise to B-cell lymphoma, thus studying these mutations can provide insight into fundamental mechanisms underlying epigenetic regulation of gene expression as well as GC B-cell and lymphoma biology. Here we show that classes of mutations in the CREBBP lysine acetyltransferase gene result in different structure, catalytic activity and function. We discover that CREBBP and its paralog EP300 are dynamically and reciprocally loaded onto chromatin during a signal-responsive cell state transitions within the GC. Mutation of CREBBP in GC-derived lymphoma interrupt signal-responsive CREBBP loading onto chromatin, while also inhibiting EP300 redundancy. These observations lead to a model in which CREBBP or EP300 loss of function through acetyltransferase domain mutations, which occur frequently in both hematopoietic and solid tumors, create a zombie enzyme that retards the function of the active paralog by binding limiting concentrations of transcription factor substrate and preventing signal-responsive enhancer activation.

cancer biology↗

bioRxiv2023

Inferring the Hoxa1 Gene Regulatory Network in Mouse Embryonic Stem Cells: Time-Series RNA-seq Data and Computational Modeling Approach

The homeotic gene Hoxa1 plays a pivotal role in regulating embryonic pattern formation and morphogenesis during mouse embryogenesis. However, despite the identification of a number of putative Hoxa1 target genes, the intricate regulatory relationships between these targets remain largely elusive. Leveraging the advancements in high-throughput technologies and sophisticated computational methods, we aimed to infer the Gene Regulatory Networks (GRNs) governed by Hoxa1 that direct cellular function, morphology, and/or differentiation. To achieve this, we generated time-series RNA-seq data from Retinoic Acid (RA)-treated Wild Type versus Hoxa1-null mouse ES cells, enabling the construction of the Hoxa1 GRN. To create this GRN, we employed NARROMI, a published technique known for its noise reduction capabilities and improved accuracy in gene-regulation inference. Using this technique, we identified putative direct and indirect connections between Hoxa1 and a set of genes with known relevance in embryonic development. Validation through qPCR confirmed the Hoxa1-dependence on mRNA expression for selected genes, both within the immediate vicinity (direct) and in secondary interactions (indirect). Furthermore, by mapping the candidate genes to relevant Gene Ontology (GO) networks, we verified their involvement in processes likely regulated by Hoxa1. Our findings provide compelling evidence supporting the accuracy of the NARROMI analysis in generating a hierarchical network of genes under the transcriptional control of Hoxa1 Transcription Factor (TF), specifically in mouse ES cells. This network reveals a pool of promising candidate genes that may function as direct targets of Hoxa1. However, further investigations, including the characterization of Hoxa1 protein interactions with target loci DNA, are necessary to confirm their direct regulatory relationship with this TF. Moreover, the time-series RNA-seq data from Wild Type ES cells, coupled with the methodology employed in this study, hold the potential for constructing GRNs for additional TFs activated by RA. This comprehensive approach can shed further light on the intricate regulatory networks governing cellular function, morphology, and differentiation, advancing our understanding of embryonic development and gene regulation processes.

bioinformatics↗

bioRxiv2023

Nitrite secretion by cyanobacteria is controlled by the small protein NirP1

When the supply of inorganic carbon is limiting, photosynthetic cyanobacteria excrete nitrite, a toxic intermediate in the ammonia assimilation pathway from nitrate. While it has been hypothesized that the secreted nitrite represents excess nitrogen that could not be further assimilated due to the missing carbon, the underlying molecular mechanism has remained enigmatic. Here, we characterized a hitherto unannotated gene with homologs in the genomes of 485 different cyanobacteria that is upregulated under low carbon conditions and controlled by the transcription factor NtcA, a central regulator of nitrogen homeostasis. To understand its function, we ectopically overexpressed it in Synechocystis sp. PCC 6803, which resulted in a chlorotic phenotype, delayed growth, severe changes in amino acid pools, and nitrite excretion. Coimmunoprecipitation experiments revealed that this protein targets nitrite reductase, a central enzyme in the assimilation of ammonia from nitrate/nitrite, and was re-named to nitrite reductase regulator protein 1 (NirP1). Our results reveal that NirP1 is widely conserved in cyanobacteria and plays a crucial role in the coordination of C/N primary metabolism by targeting one of the central enzymes. In natural environments, the excreted nitrite will be utilized by other microorganisms; therefore, NirP1 ultimately impacts the activities and composition of the surrounding microbiome.

microbiology↗

bioRxiv2023

Single-chain fluorescent integrators for mapping G-protein-coupled receptor agonists

GPCRs transduce the effects of many neuromodulators including dopamine, serotonin, epinephrine, acetylcholine, and opioids. The localization of synthetic or endogenous GPCR agonists impacts their action on specific neuronal pathways. In this paper, we show a series of single-protein chain integrator sensors to determine GPCR agonist localization in the whole brain. We previously engineered integrator sensors for the mu and kappa opioid receptor agonists called M- and K-SPOTIT, respectively. Here, we show a new integrator sensor design platform called SPOTall that we used to engineer sensors for the beta-2-adrenergic receptor (B2AR), the dopamine receptor D1, and the cholinergic receptor muscarinic 2 agonists. For multiplexed imaging of SPOTIT and SPOTall, we engineered a red version of the SPOTIT sensors. Finally, we used M-SPOTIT and B2AR-SPOTall to detect morphine, isoproterenol, and epinephrine in the mouse brain. The SPOTIT and SPOTall sensor design platform can be used to design a variety of GPCR integrator sensors for unbiased agonist detection of many synthetic and endogenous neuromodulators across the whole brain.

bioengineering↗

bioRxiv2023

A novel phenylpropanoid methyl esterase enables catabolism of aromatic compounds that inhibit biological nitrification

Agriculture is the largest source of greenhouse gases (GHG) production. Conversion of nitrogen fertilizers into more reduced forms by microbes through a process known as biological nitrification drives GHG production, enhances proliferation of toxic algal blooms, and increases cost of crop production. Some plants reduce biological nitrification in soils by exuding a diverse array of biological nitrification inhibitors (BNIs) that inhibit the ammonium oxidizing microbes responsible for nitrification. Applying synthetic biology to enhance and transfer BNI production into food and bioenergy crops is a promising approach to reduce nitrification but the success of this strategy is contingent upon improving our limited understanding of BNIs mechanisms-of-action and degradation in the soil. We addressed this gap by investigating the previously unknown metabolic route through which a prominent class of aromatic BNIs known as phenylpropanoid methyl esters (PPMEs) are catabolized. While neither transcriptomics (RNAseq) or high-throughput functional genomics (RB-TnSeq) methods reduced the genetic search space for pathway discovery into a tenable number of genes, the combination of narrowed the search space to a collection of 4 proteins of unknown function. Using genetic and biochemical analyses we found that two previously uncharacterized enzymes, including a novel phenylpropanoid methyl esterase, funnel PPMEs into an established phenylpropanoid catabolism pathway. Transfer of these two enzymes into bacteria capable of using other phenylpropanoids use of PPMEs as carbon sources. This work both provided insight into BNI catabolism and is the first step towards development of model in vivo plant-microbe systems for studying BNI mechanisms under well controlled conditions.

microbiology↗

bioRxiv2023

Defined synthetic microbial communities colonize and benefit field-grown sorghum

The rhizosphere represents a dynamic and complex interface between plant hosts and the microbial community found in the surrounding soil. While it is recognized that manipulating the rhizosphere has the potential to improve plant fitness and health, engineering the rhizosphere microbiome through inoculation has often proved challenging. This is in large part due to the competitive microbial ecosystem in which the added microbes must survive, and lack of adaptation of these added microbes to the specific metabolic and environmental pressures of the rhizosphere. Here, we constructed an inoculation formula using a defined synthetic community (dSynCom) approach that we hypothesized would improve engraftment efficiency and potentially the relationship with the host plant, Sorghum bicolor. The dSynCom was assembled from bacterial isolates that were either: 1) identified to potentially play a role in community cohesion through network analysis, or 2) identified to benefit from host-specific exudate compounds. Growth of the dSynCom was first evaluated in vitro on solid media, secondly in planta under gnotobiotic laboratory conditions, and finally using sorghum plants grown in the field. We demonstrate that the dSynCom performs best in terms of maintaining diversity when grown in the presence of the plant host in lab conditions, and that many lineages are lost from the community when grown either in vitro or in a native field setting. Finally, we demonstrate that the dSynCom is able to promote growth of above- and below-ground plant phenotypes compared to uninoculated controls, both in the lab and when applied to plants grown in the field. These results demonstrate the potential utility of SynComs for supporting crop performance even in the absence of persistence, and the need for a deeper mechanistic understanding of community control of host fitness in agricultural contexts.

synthetic biology↗

bioRxiv2023

Sorgoleone degradation by sorghum-associated bacteria; an opportunity for enforcing plant growth promotion

Metabolite exchange between plant roots and their associated rhizosphere microbiomes underpins plant growth promotion by microbes. Sorghum bicolor is a cereal crop that feeds animals and humans and is used for bioethanol production. Its root tips exude large amounts of a lipophilic benzoquinone called sorgoleone. Sorgoleone is an allelochemical that suppresses the growth of competing plant seedlings and is mineralized by microbes in soil. As an avenue to understand how sorghum and its root microbiome may be connected through root exudates, we identified the molecular determinants of microbial sorgoleone degradation and the distribution of this trait among microbes. We isolated and studied from sorghum-associated soils, three bacterial strains classified as Acinetobacter, Burkholderia, and Pseudomonas species that grow with sorgoleone as a sole carbon and energy source. The genomes of these strains were sequenced and subjected to transcriptomic and gene fitness analyses to identify candidate sorgoleone degradation genes. Follow up mutational analysis showed that sorgoleone catabolism is dependent on four contiguous genes that are conserved among the species we sequenced. Phylogenetic analysis of the sorgoleone degradation gene cluster showed that sorgoleone catabolism is enriched in sorghum-associated Streptomyces strains. The discovery of bacteria that grow on a compound like sorgoleone that is plant specific and not widely distributed in the environment, provides an opportunity to study how a plant exudate can enforce the development of a rhizosphere specific microbiome for the mutual benefit of plant and microbe. SignificanceThe grain crop sorghum exudes an herbicidal compound called sorgoleone from its root tips, which inhibits the growth of other plants. We isolated bacteria that grow on sorogleone and identified a cluster of bacterial genes required for sorogleone degradation that can be used as a biomarker for this trait. An approach to improve the production of crops in stressful conditions such as drought, is to encourage their association with plant growth promoting bacteria. Our discovery of sorgoleone degradation genes opens the door to engineering bacteria that receive benefit from sorghum in the form of a plant-specific growth substrate, and in return promote the growth of this crop.

microbiology↗

bioRxiv2023

Atypical beta-band effects in children with dyslexia in response to rhythmic audio-visual speech

Children with dyslexia are known to show impairments in perceiving speech rhythm, which impact their phonological development. Neural rhythmic speech studies have reported atypical delta phase in children with dyslexia, but beta band effects have not yet been studied. It is known that delta phase modulates the amplitude of the beta band response during rhythmic tasks via delta-beta phase-amplitude coupling (PAC). Accordingly, the atypical delta band effects reported for children with dyslexia may imply related atypical beta band effects. Here we analyse EEG data collected during a rhythmic speech paradigm from 51 children (21 typically-developing; 30 with dyslexia) who attended to a talking head repeating "ba" at 2Hz. Phase entrainment in the beta band, angular velocity in the beta band, power responses in the beta band and delta-beta PAC were assessed for each child and each group. Phase entrainment in the beta band was only significant for children without dyslexia. Children with dyslexia did not exhibit any phase consistency, and beta-band angular velocity was significantly faster compared to control children. Power in the beta band was significantly greater in the children with dyslexia. Delta-beta PAC was significant in both groups. The data are interpreted with respect to temporal sampling theory.

neuroscience↗

bioRxiv2022

Alpha suppression during prehension indicates neural motor drive inhibition

Changes in alpha band activity (8-12 Hz) have been shown to indicate the inhibition of engagement of brain regions during cognitive tasks, reflecting real-time cognitive load. Despite this, its feasibility to be used in a more dynamic environment with ongoing motor corrections has not been studied. This research used electroencephalography (EEG) to explore how different brain regions are engaged during a simple grasp and lift task where unexpected changes to the objects properties are introduced. To our knowledge, this is the first study to show alpha activity changes related to motor error correction occur only in motor-related areas (i.e. central areas), but not in error processing areas (ie. fronto-parietal network). This suggests that oscillations over motor areas could reflect inhibition of motor drive related to motor error correction, thus being a potential cortical electrophysiological biomarker for the process, and not solely as a proxy for cognitive demands. This observation is particularly relevant in scenarios where these signals are used to evaluate high cognitive demands co-occurring with high levels of motor errors and corrections, such as prosthesis use. The establishment of electrophysiological biomarkers of mental resource allocation during movement and cognition can help identify indicators of mental workload and motor drive, which may be useful for improving brain-machine interfaces. New and NoteworthyThis research expands on previous fMRI literature by demonstrating that alpha band suppression, an EEG metric with high temporal resolution, occurs over the primary sensorimotor area during error correction of hand movements. This furthers our understanding of alpha suppression beyond processes related to cognitive demands by highlighting how motor control also influences this frequency band. Recognizing that alpha band activity is modulated by both motor and cognitive processes is important in situations where high cognitive demands can lead to a high level of movement errors. Interpretations of such modulation are often attributed only to cognitive demands, whereas a motor process may also play a factor. Furthermore, alpha suppression could be used as a biomarker for error correction with applications in human machine interfaces, such as neuroprostheses.

neuroscience↗

bioRxiv2022

Misaligned plastic and evolutionary responses of lifespan to novel carbohydrate diets

Diet elicits varied effects on longevity across a wide range of animal species. For example, diets low in protein and high in carbohydrate typically extend lifespan while diets high in protein tend to reduce it. Although studies have also shown that diet-induced lifespan changes can persist through transgenerational plasticity, whether such changes lead to evolutionary shifts in lifespan remains unclear. In this study we combine experimental evolution and phenotypic plasticity assays to address this gap. Using Drosophila serrata, we investigated the evolutionary potential of lifespan in response to four novel diets spanning a carbohydrate-protein gradient. We also examined developmental plasticity effects using a set of control populations that were raised on the four novel environments. Our results show that although lifespan evolved in response to changes in dietary carbohydrate concentration, the plastic responses for lifespan differed from the evolved responses. The direction of the evolved response (increased lifespan) observed on low carbohydrate diets was in the opposite direction to the plastic response (decreased lifespan). Our results imply that plastic responses to low carbohydrates can be maladaptive for lifespan and misaligned with the evolved responses, laying the groundwork for future investigations of carbohydrate contributions to evolved and plastic effects on lifespan.

evolutionary biology↗

bioRxiv2022

Atypical cortical encoding of speech identifies children with Dyslexia versus Developmental Language Disorder

Slow cortical oscillations play a crucial role in processing the speech envelope, which is perceived atypically by children with Developmental Language Disorder (DLD) and developmental dyslexia. Here we use electroencephalography (EEG) and natural speech listening paradigms to identify neural processing patterns that characterize dyslexic versus DLD children. Using a story listening paradigm, we show that atypical power dynamics and phase-amplitude coupling between delta and theta oscillations characterize dyslexic and DLD children groups, respectively. We further identify EEG common spatial patterns (CSP) during speech listening across delta, theta and beta oscillations describing dyslexic versus DLD children. A linear classifier using four deltaband CSP variables predicted dyslexia status (0.77 AUC). Crucially, these spatial patterns also identified children with dyslexia in a rhythmic syllable task EEG, suggesting a core developmental deficit in neural processing of speech rhythm. These findings suggest that there are distinct atypical neurocognitive mechanisms underlying dyslexia and DLD.

neuroscience↗

bioRxiv2022

Treatment with anti-inflammatory viral serpin modulates immuno-thrombotic responses and improves outcomes in SARS-CoV-2 infected mice

1.Severe acute respiratory distress syndrome (ARDS) during SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) infection, manifests as uncontrolled lung inflammation and systemic thrombosis with high mortality. Anti-viral drugs and monoclonal antibodies can reduce COVID-19 severity if administered in the early viremic phase, but treatments for later stage immuno-thrombotic syndrome and long COVID are limited. Serine protease inhibitors (SERPINS) regulate activated proteases during thrombotic, thrombolytic and immune responses. The myxoma poxvirus-derived Serp-1 protein is a secreted immunomodulatory serpin that targets activated coagulation and complement protease pathways as part of a self-defense strategy to combat viral clearance by the innate immune system. When purified and utilized as an anti-immune therapeutic, Serp-1 is effective as an anti-inflammatory drug in multiple animal models of inflammatory lung disease and vasculitis. Here, we describe systemic treatment with purified PEGylated Serp-1 (PEGSerp-1) as a therapy for immuno-thrombotic complications during ARDS. Treatment with PEGSerp-1 in two distinct mouse-adapted SARS-CoV-2 models in C57Bl/6 and BALB/c mice reduced lung and heart inflammation, with improved clinical outcomes. PEGSerp-1 significantly reduced M1 macrophage invasion in the lung and heart by modifying urokinase-type plasminogen activator receptor (uPAR) and complement membrane attack complex (MAC). Sequential changes in urokinase-type plasminogen activator receptor (uPAR) and serpin gene expression were observed in lung and heart with PEGSerp-1 treatment. PEGSerp-1 is a highly effective immune-modulator with therapeutic potential for treatment of severe viral ARDS with additional potential to reduce late SARS-CoV-2 complications related to immune-thrombotic events that persist during long COVID. SignificanceSevere acute respiratory distress syndrome (ARDS) in SARS-CoV-2 infection manifests as uncontrolled tissue inflammation and systemic thrombosis with high mortality. Anti-viral drugs and monoclonal antibodies reduce COVID-19 severity if administered early, but treatments for later stage immuno-thrombosis are limited. Serine protease inhibitors (SERPINS) regulate thrombotic, thrombolytic and complement pathways. We investigate here systemic treatment with purified poxvirus-derived PEGSerp-1 as a therapeutic for immuno-thrombotic complications in viral ARDS. PEGSerp-1 treatment in two mouse-adapted SARS-CoV-2 models (C57Bl/6 and BALB/c) significantly reduced lung and heart inflammation and improved clinical outcomes, with sequential changes in thrombolytic (uPAR) and complement expression. PEGSerp-1 is a highly effective immune-modulator with therapeutic potential for immune-thrombotic complications in severe viral ARDS and has potential benefit for long COVID.

microbiology↗