Biology subjects

Cole, J.

Publications and source records attributed to Cole, J..

At least 19 recordsLinked to original sources

bioRxiv2026

Synovial lining expressed mechanosensor PIEZO1 drives inflammation-permissive macrophage phenotypes and joint inflammation

Synovial tissue-resident macrophages regulate immune homeostasis within the joint, but can adopt an inflammation-permissive phenotype that promotes immune cell infiltration in rheumatoid arthritis (RA). Understanding the factors that drive this phenotypic switch may help prevent the localisation of inflammation in the joints of individuals at-risk of RA. We identified the mechanosensitive ion channel PIEZO1 as a potential regulator of lining-layer synovial tissue macrophage (STM) function. PIEZO1 was highly expressed in homeostatic, tissue resident TREM2pos lining-layer STMs and in its pathogenic chemokine producing TREM2low phenotype that characterises the hyperplastic lining-layer in active RA. Intra-articular injection of a PIEZO1 agonist in mice induced neutrophil and monocyte infiltration, whereas inhibition of PIEZO1 signalling restored the protective macrophage phenotype. Thus, mechanosensing via PIEZO1 is a defining feature of the joint lining-layer, and its aberrant activation by mechanical stress may lead to the localisation of inflammation within the joint, facilitating a transition from asymptomatic autoimmunity of at-risk RA to clinical disease.

immunology↗

bioRxiv2025

Central role for fast nociceptors in mechanical nocifensive behavior and sensitization

Nociceptors, primary afferent nerve fibers that signal noxious stimuli, are broadly divided into slowly conducting unmyelinated C fibers and fast-conducting myelinated A fibers. Whereas C-nociceptors have been extensively studied, considerably less is known about the function of A-nociceptors. To address this gap, we developed an intersectional genetic approach for robust and selective interrogation and manipulation of mechanically responsive A-nociceptors (A-MNs) in mice. Optogenetic A-MN stimulation induced rapid and precise withdrawal reflexes as well as place aversion and facial expression changes consistent with pain affect, while inhibition strongly impaired mechanical nociceptive withdrawal reflexes, demonstrating that A-MNs are necessary and sufficient for rapid avoidance of noxious mechanical stimuli. Prolonged A-MN activation induced mechanical allodynia and central sensitization. In a rare individual lacking thickly myelinated A{beta} fibers, mechanical withdrawal reflexes were completely absent, and pain perception reduced. Together, these findings identify fast-conducting mechano-nociceptors as essential drivers of nocifensive behaviors in mice and humans.

neuroscience↗

bioRxiv2025

PhyloAug: An Evolutionary and Structure-Aware Data Augmentation Tool

Genomic Language Models (GLMs) suffer from the inherent problem of data scarcity, due to the cost, time and complexity of wet-lab experiments. Data augmentation offers a solution; however traditional methods may unintentionally affect the underlying structure or function. By combining evolutionary signals with the RNA secondary structure, augmentations can retain original function, and remain structurally coherent. To implement this, we developed PhyloAug, a structure-aware, evolution-inspired augmentation method grounded in neutral theory. We employ Genomic Foundation Models (GFMs) to accurately perturb RNA sequences, and utilise phylogenetic analysis via PAML to provide site-wise restrictions based on evolutionary principles. These principles are obtained through the identification of evolutionarily neutral sites (sequence positions where mutations are unlikely to alter function), which are concatenated with the predicted (or known) secondary structure. We thereby ensure adherence to the underlying structure whilst enabling biologically plausible variation. To validate the biological validity of our augmentations, we compare our predicted neutral sites with Rfam-annotated conserved regions and assess sequence similarity to the underlying multiple sequence alignments. We next fine-tune GLMs on augmented data, yielding significant performance improvements up to 12.9% MCC, and 17.2% F1-Score.

bioinformatics↗

bioRxiv2025

CLONEID: A Framework for Monitoring and Steering Subclonal Dynamics

Molecular assays can resolve clonal structure, but they are expensive and typically sparse in time, whereas phenotypic observations such as imaging can be collected frequently but often are not preserved in the context needed for later interpretation. We present CLONEID, an event-based framework for organizing clone-resolved phenotypic, molecular, and specimen-context records so that genotype-to-phenotype interpretation can be maintained across time. CLONEID links time-stamped Events, assay-specific Perspectives, and reconciled Identities through structured ingestion, provenance-aware retrieval, and reproducible export, complementing upstream clone-calling methods. In a long-term gastric cancer density-selection experiment, CLONEID linked repeated culture events, growth measurements, and late karyotypic profiling within a shared record, supporting longitudinal interpretation of phenotypic adaptation together with underlying chromosomal state.

bioinformatics↗

bioRxiv2025

Mapping gene expression across the microbiome-gut-brain axis of germ- and specific pathogen-free mice

Perturbation of the gut microbiota has been implicated in neurological diseases via communication across the microbiome-gut-brain axis. As a result, the discovery of mechanisms underlying interaction across this axis are becoming increasingly important. The germ-free (GF) mouse model has enabled an improved understanding of the influence of the gut microbiota on brain development and function. By utilising an advanced spatial profiling approach, we determined transcriptional changes in the brain, improving our understanding of how brain cells function and interact within their microenvironment in the absence of microbiome influence. Targeted regions of interest were selected based on brain regions implicated in neurological disease or reported structural differences between GF mouse brains and those of colonized mice. In the hippocampus 276 differentially expressed genes (DEGs) were identified, 345 DEGs in the thalamus, and 21 DEGs in pons. Contrastingly we identified only 2 DEGs in the midbrain and 4 in the medulla oblongata, with no DEGs in the cerebellum or corpus callosum. This data provides an overview of gut microbiota influence on gene expression in the brain, highlighting multiple genes of interest for further investigation in the context of microbiome influence on brain function and their potential relevance to neurological disease.

microbiology↗

bioRxiv2024

Comparative genomic analysis of a metagenome-assembled genome reveals distinctive symbiotic traits in a Mucoromycotina fine root endophyte arbuscular mycorrhizal fungus

BackgroundRecent evidence shows that arbuscular mycorrhizal (AM) symbiosis is established by two distinct fungal groups, with the distinctive fine root endophyte morphotype formed by fungi from the sub-phylum Mucoromycotina rather than the sub-phylum Glomeromycotina. While Mucoromycotina AM fungi are globally distributed, there is currently no understanding of the genomic basis for their symbiosis or how this symbiosis compares to that of other mycorrhizal symbionts. ResultsWe used culture-independent metagenome sequencing to assemble and characterise the metagenome-assembled genome (MAG) of a putative fine root endophyte, which we show belonged to the family Planticonsortiaceae within the order Densosporales. The MAG shares key traits with Glomeromycotina fungi, which indicate obligate biotrophy, including the absence of fatty acid and thiamine biosynthesis pathways, limited enzymatic abilities to degrade plant cell walls, and a high abundance of calcium transporters. In contrast to Glomeromycotina fungi, it exhibits a higher capacity for degradation of microbial cell walls, a complete cellulose degradation pathway, low abundances of copper, nitrate and ammonium transporters, and a complete pathway for vitamin B6 biosynthesis. ConclusionThese differences highlight the potential for contrasting interactions between Mucoromycotina and Glomeromycotina AM fungi with their host plant and the environment which could support niche differentiation and complementary ecological functions.

microbiology↗

bioRxiv2024

The evolution and developmental dynamics of histone-based chromatin regulation in Annelida

Eukaryotic histones protect and package nuclear DNA into nucleosomes. The dynamic addition and removal of posttranslational modifications on these proteins define regulatory regions that play a central role in genome and chromatin biology. However, our understanding of these regulatory mechanisms in animals is largely based on a few model systems, which prevents a general understanding of how histone-based regulation unfolds and promotes phenotypic variation during animal embryogenesis. Here, we apply a comprehensive multi-omics approach to dissect the histone-based regulatory complement in Annelida, one of the largest invertebrate phyla. Annelids exhibit a conserved histone repertoire organised in clusters of dynamically regulated, hyperaccessible chromatin. However, unlike other animals with reduced genomes, the worm Dimorphilus gyrociliatus shows a dramatically streamlined histone repertoire, revealing that genome compaction has lineage-specific effects on histone-based regulation. Notably, the annelid Owenia fusiformis has two H2A.X variants that co-occur in other animals, whose functional implications are unclear but represent a unique case of widespread parallel evolution of a histone variant in Eukarya. Histone-modifying enzyme complements are largely conserved amongst annelids. Yet, temporal differences in the expression of a reduced set of histone modifiers correlate with distinct ontogenetic traits and variation in the adult landscapes of histone modifications, as revealed by quantitative mass spectrometry in O. fusiformis and Capitella teleta. Collectively, our unparalleled analysis of histone-based epigenetics within a non-model phylum informs the evolution of histone-based regulation, presenting a framework to explore how this fundamental genome regulatory layer contributes to developmental and morphological diversification in annelids and animals generally.

evolutionary biology↗

bioRxiv2024

Stratifying macrophages based on their infectious burden identifies novel host targets for intervention during Crohns disease associated adherent-invasive Escherichia coli infection

Bacterial infection is a dynamic process resulting in a heterogenous population of infected and uninfected cells. These cells respond differently based on their bacterial load and duration of infection. In the case of infection of macrophages with Crohns disease (CD) associated adherent-invasive Escherichia coli (AIEC), understanding the drivers of pathogen success may allow targeting of cells where AIEC replicate to high levels. Here we show that stratifying immune cells based on their bacterial load identifies novel pathways and therapeutic targets not previously associated with AIEC when using a traditional homogeneous infected population approach. Using flow cytometry-based cell sorting we stratified cells into those with low or high intracellular pathogen loads, or those which were bystanders to infection. Immune cells transcriptomics revealed a diverse response to the varying levels of infection while pathway analysis identified novel intervention targets that were directly related to increasing intracellular AIEC numbers. Chemical inhibition of identified targets reduced AIEC intracellular replication or inhibited secretion of tumour necrosis factor alpha (TNF), a key cytokine associated with AIEC infection. Our results have identified new avenues of intervention in AIEC infection that may also be applicable to CD through the repurposing of already available inhibitors. Additionally, they highlight the applicability of immune cell stratification post-infection as an effective approach for the study of microbial pathogens.

microbiology↗

bioRxiv2023

Syndrome-informed phenotyping identifies a polygenic background for achondroplasia-like facial variation in the general population

Human craniofacial shape is highly variable yet highly heritable with genetic variants interacting through multiple layers of development. Here, we hypothesize that Mendelian phenotypes represent the extremes of a phenotypic spectrum and, using achondroplasia as an example, we introduce a syndrome-informed phenotyping approach to identify genomic loci associated with achondroplasia-like facial variation in the normal population. We compared three-dimensional facial scans from 43 individuals with achondroplasia and 8246 controls to calculate achondroplasia-like facial scores. Multivariate GWAS of the control scores revealed a polygenic basis for normal facial variation along an achondroplasia-specific shape axis, identifying genes primarily involved in skeletal development. Jointly modeling these genes in two independent control samples showed craniofacial effects approximating the characteristic achondroplasia phenotype. These findings suggest that both complex and Mendelian genetic variation act on the same developmentally determined axes of facial variation, providing new insights into the genetic intersection of complex traits and Mendelian disorders.

genetics↗

bioRxiv2023

PIEZO2-dependent rapid pain system in humans and mice.

The PIEZO2 ion channel is critical for transducing light touch into neural signals but is not considered necessary for transducing acute pain in humans. Here, we discovered an exception - a form of mechanical pain evoked by hair pulling. Based on observations in a rare group of individuals with PIEZO2 deficiency syndrome, we demonstrated that hair-pull pain is dependent on PIEZO2 transduction. Studies in control participants showed that hair-pull pain triggered a distinct nocifensive response, including a nociceptive reflex. Observations in rare A{beta} deafferented individuals and nerve conduction block studies in control participants revealed that hair-pull pain perception is dependent on A{beta} input. Single-unit axonal recordings revealed that a class of cooling-responsive myelinated nociceptors in human skin is selectively tuned to painful hair-pull stimuli. Further, we pharmacologically mapped these nociceptors to a specific transcriptomic class. Finally, using functional imaging in mice, we demonstrated that in a homologous nociceptor, Piezo2 is necessary for high-sensitivity, robust activation by hair-pull stimuli. Together, we have demonstrated that hair-pulling evokes a distinct type of pain with conserved behavioral, neural, and molecular features across humans and mice.

neuroscience↗

bioRxiv2023

Interactions between ploidy and resource availability shape clonal interference at initiation and recurrence of glioblastoma

Glioblastoma (GBM) is the most aggressive form of primary brain tumor. Complete surgical resection of GBM is almost impossible due to the infiltrative nature of the cancer. While no evidence for recent selection events have been found after diagnosis, the selective forces that govern gliomagenesis are strong, shaping the tumors cell composition during the initial progression to malignancy with late consequences for invasiveness and therapy response. We present a mathematical model that simulates the growth and invasion of a glioma, given its ploidy level and the nature of its brain tissue micro-environment (TME), and use it to make inferences about GBM initiation and response to standard-of-care treatment. We approximate the spatial distribution of resource access in the TME through integration of in-silico modelling, multi-omics data and image analysis of primary and recurrent GBM. In the pre-malignant setting, our in-silico results suggest that low ploidy cancer cells are more resistant to starvation-induced cell death. In the malignant setting, between first and second surgery, simulated tumors with different ploidy compositions progressed at different rates. Whether higher ploidy predicted fast recurrence, however, depended on the TME. Historical data supports this dependence on TME resources, as shown by a significant correlation between the median glucose uptake rates in human tissues and the median ploidy of cancer types that arise in the respective tissues (Spearman r = -0.70; P = 0.026). Taken together our findings suggest that availability of metabolic substrates in the TME drives different cell fate decisions for cancer cells with different ploidy and shapes GBM disease initiation and relapse characteristics.

cancer biology↗

bioRxiv2023

Engineering cGAS-agonistic oligonucleotides as therapeutics and vaccine adjuvants for cancer immunotherapy

Current cancer immunotherapy (e.g., immune checkpoint blockade (ICB)) has only benefited a small subset of patients. Cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) activation holds the potential to improve cancer immunotherapy by eliciting type-I interferon (IFN-I) responses in cancer cells and myeloid cells. Yet, current approaches to this end, mostly by targeting STING, have marginal clinical therapeutic efficacy. Here, we report a cGAS-specific agonistic oligonucleotide, Svg3, as a novel approach to cGAS-STING activation for versatile cancer immunotherapy. Featured with a hairpin structure with consecutive guanosines flanking the stem, Svg3 binds to cGAS and enhances cGAS-Svg3 phase separation to form liquid-like droplets. This results in cGAS activation by Svg3 for robust and dose-dependent IFN-I responses, which outperforms several state-of-the-art STING agonists in murine and human immune cells, and human tumor tissues. Nanocarriers efficiently delivers Svg3 to tissues, cells, and cytosol where cGAS is located. Svg3 reduces tumor immunosuppression and potentiates ICB therapeutic efficacy of multiple syngeneic tumors, in wildtype but neither cGas-/- nor goldenticket Sting-/- mice. Further, as an immunostimulant adjuvant, Svg3 enhances the immunogenicity of peptide antigens to elicit potent T cell responses for robust ICB combination immunotherapy of tumors. Overall, cGAS-agonistic Svg3 is promising for versatile cancer combination immunotherapy.

bioengineering↗

bioRxiv2023

Implicit motor adaptation and perceived hand position without proprioception: A kinesthetic error may be derived from efferent signals

Implicit sensorimotor adaptation keeps our movements well-calibrated amid changes in the body and environment. We have recently postulated that implicit adaptation is driven by a perceptual error: the difference between the desired and perceived movement outcome. According to this perceptual re-alignment model, implicit adaptation ceases when the perceived movement outcome - a multimodal percept determined by a prior belief conveying the intended action, the motor command, and feedback from proprioception and vision - is aligned with the desired movement outcome. Here, we examined the role of proprioception in implicit motor adaptation and perceived movement outcome by examining individuals who lack proprioception. We used a modified visuomotor rotation task designed to isolate implicit adaptation and probe perceived outcome throughout the experiment. Surprisingly, implicit adaptation and perceived outcome were minimally impacted by deafferentation, posing a challenge to the perceptual re-alignment model of implicit adaptation.

neuroscience↗

bioRxiv2022

An intact S-layer is advantageous to Clostridioides difficile within the host.

Clostridioides difficile is responsible for substantial morbidity and mortality in antibiotically-treated, hospitalised, elderly patients, in which toxin production correlates with diarrhoeal disease. While the function of these toxins has been studied in detail, the contribution of other factors, including the paracrystalline surface layer (S-layer), to disease is less well known. Here, we highlight the essentiality of the S-layer in vivo by reporting the recovery of S-layer revertants, following infection with the S-layer-null strain, FM2.5. Sequencing of the slpA gene revealed either correction of the original point mutation or modification of the sequence upstream of the mutation, which restored the reading frame, and translation of slpA. Selection of these strains was rapid, with up to 90% of isolates identified as revertants 24 h post infection. Two revertant isolates, RvA and RvB, showed modification of 3 and 13 amino acids respectively, compared to wild type sequence. Structural determination of SlpA from RvB revealed a different orientation of its domains, resulting in a reorganisation of the lattice assembly and changes in interacting interfaces which might result in functional differences. These revertants showed differing patterns of disease in vivo; RvA causing equivalent severity to R20291 and RvB an attenuated FM2.5-like phenotype. Comparative RNA sequencing (RNA-Seq) analysis of in vitro grown isolates showed large changes in differentially expressed genes (DEGs) between R20291 and FM2.5 namely in TcdA/TcdB expression, in transcripts associated with sporulation and those linked to cell wall integrity, which may account for attenuation observed in vivo. In comparison, smaller differences were observed between RvA/R20291, and RvB/FM2.5 respectively, which correlated with observed disease severity in vivo. Cumulatively, these data highlight that the S-layer plays a role in C. difficile disease. Author SummaryThe S-layer of C. difficile is a paracrystalline array that covers the outer surface of the bacterial cell but its contribution to overall disease remains unclear. A previously described, spontaneous slpA-null mutant, FM2.5, with a point mutation in slpA offered an opportunity to study the role of the S-layer in vivo. Here, we confirm that this strain is less virulent in vivo despite effectively colonising the host and producing toxin. We also show in vivo selection for sequence modifications that restore slpA translation and produce an S-layer. While such modifications do not affect the overall 3D structure of individual SlpA (sub)domains, they can lead to altered orientation of the structural domains and subsequent S-layer assembly. Importantly, RNA-Seq analysis in vitro showed large differences in gene expression between FM2.5 and R20291. Detected differences in transcription of genes involved in toxin expression and sporulation suggests that the S-layer provides a selective survival advantage within the host, which contributes to disease severity.

microbiology↗

bioRxiv2022

A Large-Scale ENIGMA Multisite Replication Study of Brain Age in Depression

BackgroundSeveral studies have evaluated whether depressed persons have older appearing brains than their nondepressed peers. However, the estimated neuroimaging-derived "brain age gap" has varied from study to study, likely driven by differences in training and testing sample (size), age range, and used modality/features. To validate our previously developed ENIGMA brain age model and the identified brain age gap, we aim to replicate the presence and effect size estimate previously found in the largest study in depression to date (N=2,126 controls & N=2,675 cases; +1.08 years [SE 0.22], Cohens d=0.14, 95% CI: 0.08-0.20), in independent cohorts that were not part of the original study. MethodsA previously trained brain age model (www.photon-ai.com/enigma_brainage) based on 77 FreeSurfer brain regions of interest was used to obtain unbiased brain age predictions in 751 controls and 766 persons with depression (18-75 years) from 13 new cohorts collected from 20 different scanners. ResultsOur ENIGMA MDD brain age model generalized reasonably well to controls from the new cohorts (predicted age vs. age: r = 0.73, R2=0.47, MAE=7.50 years), although the performance varied from cohort to cohort. In these new cohorts, on average, depressed persons showed a significantly higher brain age gap of +1 year (SE 0.35) (Cohens d{square}={square}{square}.15, 95% CI: 0.05-0.25) compared with controls, highly similar to our previous finding. ConclusionsThis study further validates our previously developed ENIGMA brain age algorithm. Importantly, we replicated the brain age gap in depression with a comparable effect size. Thus, two large-scale independent mega-analyses across in total 32 cohorts and >3,400 patients and >2,800 controls worldwide show reliable but subtle effects of brain aging in adult depression.

neuroscience↗

bioRxiv2022

Climate stress and its impact on livestock health, farming livelihoods and antibiotic use in Karnataka, India

Understanding the impact of climate change on livestock health is critical to safeguarding global food supplies and economies. Informed by ethnographic research with Indian farmers, veterinarians, and poultry industry representatives, we evidence that both precipitation and vapour pressure are key climate variables that relate to outbreaks of haemorrhagic septicaemia (HS), anthrax (AX), and black quarter (BQ) across the Indian state of Karnataka. We also identify temperature and maximum temperature to be negatively correlated with the same diseases, indicating that a cooling (but still hot) climate with wetter, humid conditions is a prime risk factor for future outbreaks. Principal component analyses have revealed the SW India monsoon and winter periods to be the most strongly correlated with HS, AX and BQ outbreaks. We identify vapour pressure, a proxy for humidity, as having a positive relationship with these specific livestock diseases. The negative relationship between temperature and these diseases, combined with the positive correlation with rainfall and humidity, allow us to classify climate-associated risk using a combination of gridded meteorological time series and epidemiological outbreak data covering the same region and timespan of 1987-2020. Risk maps were constructed following concerns over the growing impact of climate pressures raised by farmers during ethnographic study. Informed by their insights, we used current climate data and future climate projections as a risk classification tool to assess how disease risk varies in Karnataka in the present and possible future scenarios. Despite a relatively limited epidemiological dataset, clear relationships between precipitation, vapour pressure, and temperature with HS, AX and BQ, along with outbreak high-risk zones were defined. This methodology can be replicated to investigate other diseases (including in humans and plants) and other regions, irrespective of scale, as long as the climate and epidemiological data cover similar time periods. This evidence highlights the need for greater consideration of climate change in One Health research and policy and puts forward a case for, we argue, greater alignment between UNFCCC and One Health policy, for example, within the Tripartite Agreement (between OIE, FOA and WHO) on antimicrobial resistance as disease risk cannot be considered independent of climate change. One Health Impact StatementThis research aims to investigate the relationship between factors related to climate (surface temperatures, rainfall, humidity) and outbreaks of livestock-related bacterial diseases. This is especially relevant to the One Health approach as it attempts to integrate findings between not only the science of disease but also the science of climate change as a driver of disease, and address problems that could arise within the public and private sectors (local farming, livestock health, government policy etc.). Providing spatial context to climate-associated disease risk across the Indian state of Karnataka will benefit local farmers that may already be, or transitioning to, more intensive livestock farming along with policy makers and private sector companies who are planning for future investments. This transdisciplinary approach springboards from ethnographic observations of famers lived experiences of challenges to their livelihoods and facilitates the use of climate datasets that may not have been primarily collected for or used by disease-related studies to map long-term epidemiological risk. This demonstrates the pragmatic impact that such transdisciplinary projects can have by providing interpretations of observed risks to animal health (highlighted by social scientists during engagement with practitioner communities) that Earth Scientists were then able to quantify, proving links that would be otherwise not have been evidenced. Using disease data sourced from local institutions, including Government of India facilitates as well academic research laboratories, can plan the application of pragmatic solutions to local farmers who are primarily impacted by the findings of the research.

scientific communication and education↗

bioRxiv2022

Systematic comparison of ranking aggregation methods for gene lists in experimental results

A common experimental output in biomedical science is a list of genes implicated in a given biological process or disease. The results of a group of studies answering the same, or similar, questions can be combined by meta-analysis to find a consensus or a more reliable answer. Ranking aggregation methods can be used to combine gene lists from various sources in meta-analyses. Evaluating a ranking aggregation method on a specific type of dataset before using it is required to support the reliability of the result since the property of a dataset can influence the performance of an algorithm. Evaluation of aggregation methods is usually based on a simulated database especially for the algorithms designed for gene lists because of the lack of a known truth for real data. However, simulated datasets tend to be too small compared to experimental data and neglect key features, including heterogeneity of quality, relevance and the inclusion of unranked lists. In this study, a group of existing methods and their variations which are suitable for meta-analysis of gene lists are compared using simulated and real data. Simulated data was used to explore the performance of the aggregation methods as a function of emulating the common scenarios of real genomics data, with various heterogeneity of quality, noise level, and a mix of unranked and ranked data using 20000 possible entities. In addition to the evaluation with simulated data, a comparison using real genomic data on the SARS-CoV-2 virus, cancer (NSCLC), and bacteria (macrophage apoptosis) was performed. We summarise our evaluation results in terms of a simple flowchart to select a ranking aggregation method for genomics data.

bioinformatics↗

bioRxiv2021

Myeloid cell interferon responses correlate with clearance of SARS-CoV-2

The emergence of mutant SARS-CoV-2 strains associated with an increased risk of COVID-19-related death necessitates better understanding of the early viral dynamics, host responses and immunopathology. While studies have reported immune profiling using single cell RNA sequencing in terminal human COVID-19 patients, performing longitudinal immune cell dynamics in humans is challenging. Macaques are a suitable model of SARS-CoV-2 infection. We performed longitudinal single-cell RNA sequencing of bronchoalveolar lavage (BAL) cell suspensions from adult rhesus macaques infected with SARS-CoV-2 (n=6) to delineate the early dynamics of immune cells changes. The bronchoalveolar compartment exhibited dynamic changes in transcriptional landscape 3 days post-SARS-CoV-2-infection (3dpi) (peak viremia), relative to 14-17dpi (recovery phase) and pre-infection (baseline). We observed the accumulation of distinct populations of both macrophages and T-lymphocytes expressing strong interferon-driven inflammatory gene signature at 3dpi. Type I IFN response was highly induced in the plasmacytoid dendritic cells. The presence of a distinct HLADR+CD68+CD163+SIGLEC1+ macrophage population exhibiting higher angiotensin converting enzyme 2 (ACE2) expression was also observed. These macrophages were significantly recruited to the lungs of macaques at 3dpi and harbored SARS-CoV-2, while expressing a strong interferon-driven innate anti-viral gene signature. The accumulation of these responses correlated with decline in viremia and recovery. The recruitment of a myeloid cell-mediated Type I IFN response is associated with the rapid clearance of SARS-CoV-2 infection in macaques.

immunology↗