SEARCH · bioRxiv Science

Results for “immunology”

Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 559 records · Page 31Linked to original sources

bioRxiv2024

Antagonizing the SAMD9 pathway is key to myxoma virus host shut-off and immune evasion.

Poxviruses have life cycles exclusively in the cytoplasm. However, these viruses can have profound impact to host transcription. One possible mechanism is through viral manipulation of host protein synthesis and such ability is critical for viral immune evasion. Many mammalian poxviruses encode more than one viral protein to interact with the host SAMD9 protein. In myxoma virus (MYXV), a rabbit specific poxvirus and non-pathogenic for other species, viral M062 protein is the lone inhibitor to SAMD9 with broad species specificity and loss of M062R in viral genome ({Delta}M062R mutant) leads to profound infection defect. We previously found {Delta}M062R remodeled transcriptomic landscape in monocytes/macrophages that is associated with the crosstalk between the SAMD9 pathway and cGAS/STING/IRF3 DNA sensing pathway. In this study we completed the characterization of {Delta}M062R infection. We observed that although this replication-defective virus preserved intact early protein synthesis, it failed to conduct host shutoff. Despite a defect in viral DNA replication, {Delta}M062R infection retained intact intermediate protein synthesis comparable to the wildtype virus. Using time course dual RNAseq analyses we found that the overall viral gene transcription profile was mostly indistinguishable from that of the wildtype MYXV. However, the slightly attenuated late RNA synthesis along with the block at viral protein synthesis led to its infection defect. Infection by {Delta}M062R in macrophages potentiated the antiviral responses to new danger signals. We provided an initial characterization of such a state in which host antiviral protein synthesis may be promoted leading to the immunological consequence. ImportancePoxviruses utilize multi-faceted strategies to evade and manipulate host immunity. Through targeted gene deletion, we generated useful tools of mutant poxviruses to investigate specific crosstalk between host defense mechanisms. Through studying MYXV M062 protein function, we previously identified SAMD9 as one host target of poxvirus C7L superfamily, in which family M062R is one member. However, what kind of cellular outcome caused by {Delta}M062R infection remained unknown. The infection defect of {Delta}M062R caused the induction of host inflammation program is likely due to the activation of the host pathway governed by SAMD9. Because little is known about SAMD9 cellular function and the pathways it regulates, which are important for cellular homeostasis and immune regulation, this study on {Delta}M062R induced effect in host cells will provide new insight on how SAMD9 affects cellular protein synthesis and immunological responses.

microbiology↗

bioRxiv2024

Immune escape of Omicron lineages BA.1, BA.2, BA.5.1, BQ.1, XBB.1.5, EG.5.1 and JN.1.1 after vaccination, infection and hybrid immunity

In the 5th year after the emergence of SARS-CoV-2, Omicron lineages continue to evolve and cause infections. Here, we used eight authentic SARS-CoV-2 isolates to assess their capacity to escape immunity of different exposure histories and their replicative capacity in polarized human airway epithelial cells (HAE) derived from the nasal and bronchial epithelium. Using live-virus neutralization assays of 108 human sera or plasma of different immunological backgrounds, progressive immune escape was observed from B.1 (ancestral virus) to EG.5.1, but no significant difference between EG.5.1 and JN.1.1. Vaccinated individuals without natural infection and individuals with a single infection, but no vaccination showed markedly reduced or completely lost neutralization against the latest variants, while in those with hybrid immunity almost all sera showed some neutralization capacity. Furthermore, although absolute titers differed between groups, the pattern of immune escape between the variants remains comparable with strongest loss of neutralization observed for the latest variants. In vitro studies with HAE at 33{degrees}C and 37{degrees}C showed some, but minor differences in virus replication and innate immune responses upon infection. Notably, infection with XBB.1.5, EG.5.1 and JN.1.1 showed slightly increased viral growth in nasal HAE at 33{degrees}C. Altogether, these data underscore increasing immune escape across heterogeneous immunological backgrounds with gradually increasing antibody escape of evolving Omicron lineages until variant EG.5.1, but not any further for the latest dominant lineage JN.1.1. They also suggest that viral dynamics within Omicron lineages are driven by a combination of immune evasion and increase in viral replication.

microbiology↗

bioRxiv2024

Canine major histocompatibility complex class I (MHC-I) diversity landscape

The genes of the Major Histocompatibility Complex class I (MHC-I) are among the most diverse in the mammalian genome, playing a crucial role in immunology. Understanding the diversity landscape of MHC-I is therefore of paramount importance. The dog is a key translational model in various biomedical fields. However, our understanding of the canine MHC-I diversity landscape lags significantly behind that of humans. To address this deficiency, we used our newly developed software, KPR de novo assembler and genotyper, to genotype 1,325 samples from 1,025 dogs with paired-end RNA-seq data from 43 BioProjects, after extensive quality control. Among 926 dogs that pass the QC, 591 dogs (64%) have at least one allele genotyped, and a total of 97 known alleles and 52 putative new alleles were identified. Further analysis reveals that DLA-I gene expression levels vary among the tissues, with lowest for testis and brain tissues and highest for blood, corpus luteum, and spleen. We identified dominant alleles in each of the 17 canine breeds, as well as among the entire canine population. Furthermore, our analysis also identifies breed-specific alleles and mutually co-occurred/exclusive alleles. Our study indicates that canine DLA-88 is as diversified as human HLA-A/B/C genes within the entire population, but less diversified within a breed than with HLA-A/B/C within an ethnic group. Lastly, we examined the hypervariable regions (HVR) within or across human/canine MHC-I alleles and found that 80% of the HVRs overlap between the two species. We further noted that 80% of the HVRs are within 4A contact with the peptides, and that the dog-human difference overlaps with only 20% HVRs. Our research offers valuable insights for immunological studies involving dogs.

bioinformatics↗

bioRxiv2024

Fitness adaptations of Japanese encephalitis virus in pigs following vector-free serial passaging

Japanese encephalitis virus (JEV) is a zoonotic mosquito-transmitted Flavivirus circulating in birds and pigs. In humans, JEV can cause severe viral encephalitis with high mortality. Considering that vector-free direct virus transmission was observed in pigs, JEV introduction into an immunologically naive pig population could result in a series of direct transmissions disrupting the alternating host cycling between vertebrates and mosquitoes. To assess the potential consequences of such a realistic scenario, we passaged JEV ten times in pigs. This resulted in higher in vivo viral replication, increased shedding, and stronger innate immune responses in pigs. Nevertheless, the viral tissue tropism remained similar and frequency of direct transmission was not enhanced. Next generation sequencing showed single nucleotide deviations in 10% of the genome during passaging. In total, 25 point mutations were selected to reach a frequency of at least 35% in one of the passages. From these, six mutations resulted in amino acid changes located in the precursor of membrane, the envelope, the non-structural 3 and the non-structural 5 proteins. In a competition experiment with two lines of passaging, the mutation M374L in the envelope protein and N275D in the non-structural protein 5 showed a fitness advantage in pigs. Altogether, the interruption of the alternating host cycle of JEV caused a prominent selection of viral quasispecies as well as selection of de novo mutations associated with fitness gains in pigs, albeit without enhancing direct transmission frequency. Author summaryJapanese encephalitis virus (JEV) represents a major health threat in parts of Asia and Oceania. Primary vertebrate hosts are birds and pigs, but human infection also occurs and can cause severe encephalitis with high mortality. Like other Flaviviruses transmitted by insect bites, JEV requires replication in alternating cycles between mosquitoes on one side and birds or pigs on the other side. However, we previously reported that direct transmissions between pigs in absence of mosquitos can occur. Considering the increased risks for such events after the spread of JEV to a new region with immunologically naive pigs, the present study was performed to understand if and how a series of direct transmissions would promote JEV adaptations to pigs and change virus-host interactions. Pigs infected with JEV passaged ten times showed enhanced clinical symptoms and stronger antiviral immune response, but luckily no increase in direct transmission was observed. Nevertheless, genomic analysis demonstrated a complete change in dominant virus variants, as well as selection of six viral amino acid changes. This indicates that interruptions of the alternating lifestyle of JEV causes a strong evolutionary pressure, which through fitness adaptations can change the viral characteristics.

microbiology↗

bioRxiv2024

Celldetective: an AI-enhanced image analysis toolfor unraveling dynamic cell interactions

Analysis of multimodal and multidimensional data capturing dynamic interactions between diverse cell populations is a current challenge in bioimaging, especially in the context of immunology and immunotherapy research. Here, we introduce Celldetective, an open-source Python-based software tool designed for high-performance, end-to-end analysis of image-based in vitro immune and immunotherapy assays. Celldetective is purpose-built for multicondition, 2D multi-channel time-lapse microscopy of mixed cell populations. Although it is optimised for the needs of immunology assays, it is nevertheless broadly applicable to any biological system involving interacting cell populations. The software seamlessly integrates AI-based segmentation, tracking, and automated single-cell event detection, all within an intuitive graphical interface that supports interactive visualisation, annotation, and training options. We showcase its capabilities with original datasets of single immune effector cell interactions with an activating surface mediated by bispecific antibodies, and pairwise interactions in antibody-dependent cell cytotoxicity events.

bioinformatics↗

bioRxiv2024

Single RNA molecule resolution spatial imaging of immunotherapy response in triple negative breast tumors harboring tertiary lymphoid structures

Cancer immunotherapy trials have had variable success, prompting a search for biomarkers of response. Tertiary lymphoid structures (TLS) have emerged as prognostic for multiple tumor types. These ectopic immunological bodies resemble secondary lymphoid organs with segregated B and T cell zones, but they are heterogeneous in their organization and cellular composition. These features have consequences in terms of prognostication and disease clearance, so there is interest in what drives TLS heterogeneity and corresponding immunological responses. We applied single RNA molecule resolution imaging to study biopsies from triple negative breast tumors harboring TLS where the biopsies were taken longitudinally, prior to therapy, after pembrolizumab and after pembrolizumab with radiation therapy. We developed a computational framework to identify TLS and tumor beds and to align spatial trajectories between the immune and malignant structures for systematic analyses. We identified two tumor types based on immune infiltration profiles in the tumor bed. Immune "infiltrated" tumors were eliminated after pembrolizumab, while "non-infiltrated" tumors saw gains in effector T cells and myeloid cells after pembrolizumab and were cleared after pembrolizumab with RT. TLS from infiltrated tumors had better separation of B and T cell zones and had higher expression of immunoreactivity gene pathways in most cell types. Further, malignant cell MHC expression was higher in the tumor beds of infiltrated tumors, providing one plausible mechanism for the groupings. In non-infiltrated tumors, classical dendritic cells enter the tumor bed from TLS proximal zones after pembrolizumab and bring transcription of the CXCL9 chemokine, which can recruit T cells and promote T cell effector phenotypes and was higher in infiltrated tumors at baseline.

genomics↗

bioRxiv2024

Optogenetics-integrated gut organ culture system connects enteric neurons dynamics and gut homeostasis

The enteric nervous system (ENS) senses microbiota-derived signals and orchestrates mucosal immunity and epithelial barrier functions, in health and disease. However, mechanistic dissections of intestinal neuro-immune-microbiota communications remain challenging and existing research methods limit experimental controllability and throughput. Here, we present a novel optogenetics-integrated gut organ culture system that enables real-time, whole-tissue stimulation of specific ENS lineages, allowing for detailed analysis of their functional impact. We demonstrate that optogenetic activation of enteric cholinergic neurons rapidly modulates intestinal physiology. Interestingly, distinct neuronal firing patterns differentially modulate neuro-immunological gene expression and epithelial barrier integrity. Furthermore, diverse enteric neuronal lineages exert distinct regulatory roles. While cholinergic activation promotes gene-sets associated with type-2 immunity, tachykininergic enteric neurons differentially control mucosal defense programs. Remarkably, luminal introduction of the immunomodulatory bacterium C. ramosum significantly remodeled cholinergic-induced neuro-immunological transcription. These findings suggest that complex combinatorial signals delivered by gut microbes and enteric neurons are locally integrated to fine-tune intestinal immunity and barrier defense. Collectively, we provide a powerful platform for systematic discovery and mechanistic exploration of functional neuroimmune connections, and their potential modulation by drugs, microbes, or metabolites. Short abstractThe enteric nervous system senses microbiota-derived signals and orchestrates mucosal immunity and epithelial barrier functions. Mechanistic dissections of intestinal neuro-immune-microbiota communications remain challenging. We developed an optogenetics-integrated gut organ culture system for real-time neuronal stimulation and analysis. We revealed neuronal-specific activity patterns, which differentially regulate intestinal transcription and epithelial barrier integrity. Collectively, we provide a powerful platform to test neuroimmune connections and their potential modulation by drugs, microbes, or metabolites.

neuroscience↗

bioRxiv2024

Lower baseline immunity in invasive Egyptian goose compared to sympatric native waterfowls

Successful invasive species increase their spreading success by trading-off nutritional and metabolic resources allocated to reproduction and range expansion with other costly body functions. One proposed mechanism for the reallocation of resources is a trade-off with the immune function and the regulation of oxidative status. Relying on a panel of blood-based markers of immune function and oxidative status quantified in an invasive species (Egyptian goose) and two native competing species (mallard and mute swan) in Germany, we tested the hypothesis that the invasive species would have (i) lower investment in immune function, (ii) lower levels of oxidative damage, and (iii) no higher antioxidant defences compared to the native species. We found lower levels of adaptive immune markers (lymphocytes and immunoglobulin Y), in the invasive species compared to the two native species. Reactive oxygen metabolites, a marker of oxidative damage, were also lower in Egyptian geese compared to the other species, while levels of antioxidants were generally similar. Mute swans showed the highest levels of heterophils, lysozymes and haemolysis among the three species, possibly due to its larger body mass. Our results point to a reduced investment in adaptive immune function in the invasive species as a possible resources-saving immunological strategy due to the loss of co-evolved parasites in the new colonised habitats, as observed in a previous study. A lower investment in immune function may benefit other energy-demanding activities, such as reproduction, dispersal, and territoriality. Research highlightsOur results point to a reduced investment in adaptive immune function in invasive Egyptian geese compared to native and sympatric waterfowl species, as a possible resources-saving immunological strategy due to the loss of co-evolved parasites in the new colonised habitats.

ecology↗

bioRxiv2024

Single molecule array measures of LRRK2 kinase activity in serum link Parkinson's disease severity to peripheral inflammation

BackgroundLRRK2-targeting therapeutics that inhibit LRRK2 kinase activity have advanced to clinical trials in idiopathic Parkinsons disease (iPD). LRRK2 phosphorylates Rab10 on endolysosomes in phagocytic cells to promote some types of immunological responses. The identification of factors that regulate LRRK2-mediated Rab10 phosphorylation in iPD, and whether phosphorylated-Rab10 levels change in different disease states, or with disease progression, may provide insights into the role of Rab10 phosphorylation in iPD and help guide therapeutic strategies targeting this pathway. MethodsCapitalizing on past work demonstrating LRRK2 and phosphorylated-Rab10 interact on vesicles that can shed into biofluids, we developed and validated a high-throughput single-molecule array assay to measure extracellular pT73-Rab10. Ratios of pT73-Rab10 to total Rab10 measured in biobanked serum samples were compared between informative groups of transgenic mice, rats, and a deeply phenotyped cohort of iPD cases and controls. Multivariable and weighted correlation network analyses were used to identify genetic, transcriptomic, clinical, and demographic variables that predict the extracellular pT73-Rab10 to total Rab10 ratio. ResultspT73-Rab10 is absent in serum from Lrrk2 knockout mice but elevated by LRRK2 and VPS35 mutations, as well as SNCA expression. Bone-marrow transplantation experiments in mice show that serum pT73-Rab10 levels derive primarily from circulating immune cells. The extracellular ratio of pT73-Rab10 to total Rab10 is dynamic, increasing with inflammation and rapidly decreasing with LRRK2 kinase inhibition. The ratio of pT73-Rab10 to total Rab10 is elevated in iPD patients with greater motor dysfunction, irrespective of disease duration, age, sex, or the usage of PD-related or anti-inflammatory medications. pT73-Rab10 to total Rab10 ratios are associated with neutrophil activation, antigenic responses, and the suppression of platelet activation. ConclusionsThe extracellular ratio of pT73-Rab10 to total Rab10 in serum is a novel pharmacodynamic biomarker for LRRK2-linked innate immune activation associated with disease severity in iPD. We propose that those iPD patients with higher serum pT73-Rab10 levels may benefit from LRRK2-targeting therapeutics to mitigate associated deleterious immunological responses.

neuroscience↗

bioRxiv2024

Spleen gene expression is associated with mercury content in three-spined stickleback populations

Mercury can be very toxic at low environmental concentrations by impairing immunological, neurological, and other vital pathways in humans and animals. Aquatic ecosystems are heavily impacted by mercury pollution, with evidence of biomagnification through the food web. We examined the effect of mercury toxicity on the spleen, one of the primary immune organs in fish, in natural populations of the three-spined stickleback (Gasterosteus aculeatus Linnaeus, 1758). Our aim was to better understand adaptation to high mercury environments by investigating transcriptomic changes in the spleen. Three stickleback populations with mean Hg muscle concentrations above and three populations with mean Hg muscle concentrations below the European Biota Quality Standard of 20 ng/g wet weight were selected from the Scheldt and Meuse basin in Belgium. We then conducted RNA sequencing of the spleen tissue of 22 females from these populations. We identified 136 differentially expressed genes between individuals from populations with high and low mean mercury content. The 129 genes that were upregulated were related to the neurological system, immunological activity, hormonal regulation, and inorganic cation transporter activity. Seven genes were downregulated and were all involved in pre-mRNA splicing. The results are indicative of our ability to detect molecular alterations in natural populations that exceed an important environmental quality standard. This allows us to assess the biological relevance of such standards, offering an opportunity to better describe and manage mercury-associated environmental health risks in aquatic populations.

ecology↗

bioRxiv2024

Barking Up the Right Tree: Immune Checkpoint Signatures of Human and Dog Cancers

In the quest for improved therapeutics targeting immune checkpoints (ICs), we turn to spontaneously developing dog (canine) cancers, which are unique models that genetically and clinically mirror human equivalents. Despite its potential, canine cancer immunology remains largely unexplored. Here, we examine the RNA-seq-based expression of 44 ICs across 14 canine cancer types and an extensive human dataset. We unveil diverse canine IC expression patterns and unique human IC signatures that reflect the histological type and primary site of cancer. We uncover a striking similarity between canine brain cancers, osteosarcoma, and their human counterparts, identifying them as prospective immunotherapy models. Four ICs--CD160, A2AR, NKG2A, and OX40--are key to the differences observed between species. Moreover, individual patient IC signatures exhibit varying alignment with their respective cancer types, a finding with profound implications for personalized human therapy. This exploration illuminates new aspects of canine and human cancer immunology, setting the stage for discoveries at their crossroads.

cancer biology↗

bioRxiv2024

Cathelicidin antimicrobial peptides mediate immune protection of marsupial neonates

Marsupial neonates are born with immature immune systems, making them vulnerable to pathogens. While neonates receive maternal protection, they can also independently combat pathogens, though the mechanisms remain unknown. Using the sugar glider (Petaurus breviceps) as a model, we investigated immunological defense strategies of marsupial neonates. Cathelicidins - a family of antimicrobial peptides expanded in the genomes of marsupials - are highly expressed in developing neutrophils. Sugar glider cathelicidins reside in two genomic clusters and their coordinated expression is achieved by enhancer sharing within clusters and long-range physical interactions between clusters. These cathelicidins modulate immune responses and have potent antimicrobial effects, sufficient to provide protection in a mouse model of sepsis. Lastly, cathelicidins have a complex evolutionary history, where marsupials and monotremes are the only tetrapods that retained two cathelicidin clusters. Thus, cathelicidins are critical mediators of marsupial immunity, and their evolution reflects the life history-specific immunological needs of these animals.

evolutionary biology↗

bioRxiv2024

Reversible Downregulation of HLA Class I in Adenoid Cystic Carcinoma

PurposeAdenoid cystic carcinoma (ACC), a rare and lethal cancer, has shown low response rates to systemic therapies, such as cytotoxic chemotherapy and immune-checkpoint inhibitors (ICIs). Despite numerous clinical trials, some employing aggressive ICI combinations, no effective treatments for patients with recurrent or metastatic adenoid cystic carcinoma have emerged, and ACC mortality rates remain stagnant. Therefore, we aimed to characterize the ACC immune landscape to understand the poor response rates to ICIs. Experimental DesignWe leveraged automated multiplex immunofluorescence (mIF), RNA in-situ hybridization, and scRNAseq Gene Expression analysis to identify pathways supporting the cold ACC immune environment and molecularly characterize ACC tumors, adjacent normal tissues, and normal tissues from regions where ACCs arise. In vitro, we treated freshly resected ACCs with interferon-{psi} or a STING agonist. ResultsmIF demonstrated that ACC tumors are immunologically cold, with few tumor- infiltrating T-lymphocytes (TILs) and low PD-L1 expression. The most striking finding, however, was a very low HLA/B2M class I expression in almost all ACCs, which was reversible through treatment with interferon-{psi} or a STING agonist. mIF and RNAseq analyses of normal tissues revealed a p63+, NFIB+, basal duct cell population with similarly low HLA/B2M class I expression. ConclusionsLow/absent HLA/B2M expression may explain ACC tumors immunologically cold status and lack of response to ICIs. Our findings suggest that the normal cell of ACC origin exists in an HLA-low state, and that pharmacologic manipulation with immune activators, such as STING agonists, can restore HLA/B2M in ACCs, creating a path to urgently needed, effective immunotherapies.

cancer biology↗

bioRxiv2024

Utilizing Protein Bioinformatics to Delve Deeper Into Immunopeptidomic Datasets

Immunopeptidomics is a growing subfield of proteomics that has the potential to shed new light on a long-neglected aspect of adaptive immunology: a comprehensive understanding of the peptides presented by major histocompatibility complexes (MHC) to T cells. As the field of immunopeptidomics continues to grow and mature, a parallel expansion in the methods for extracting quantitative features of these peptides is necessary. Currently, massive experimental efforts to isolate a given immunopeptidome are summarized in tables and pie charts, or worse, entirely thrown out in favor of singular peptides of interest. Ideally, an unbiased approach would dive deeper into these large proteomic datasets, identifying sequence-level biochemical signatures inherent to each individual dataset and the given immunological niche. This chapter will outline the steps for a powerful approach to such analysis, utilizing the Automated Immune Molecule Separator (AIMS) software for the characterization of immunopeptidomic datasets. AIMS is a flexible tool for the identification of biophysical signatures in peptidomic datasets, the elucidation of nuanced differences in repertoires collected across tissues or experimental conditions, and the generation of machine learning models for future applications to classification problems. In learning to use AIMS, readers of this chapter will receive a broad introduction to the field of protein bioinformatics and its utility in the analysis of immunopeptidomic datasets and other large-scale immune repertoire datasets.

bioinformatics↗

bioRxiv2024

Decoding Cytokine Networks in Ulcerative Colitis to Identify Pathogenic Mechanisms and Therapeutic Targets

Ulcerative colitis (UC) is a chronic inflammatory disorder of the gastrointestinal tract characterised by dysregulated cytokine signalling. Despite the advent of advanced therapies targeting cytokine signalling, treatment outcomes for UC patients remain suboptimal. Hence, there is a pressing need to better understand the complexity of cytokine regulation in UC by comprehensively mapping the interconnected cytokine signalling networks that are perturbed in UC patients. To address this, we undertook systems immunology modelling of single-cell transcriptomics data from colonic biopsies of treatment-naive and treatment-exposed UC patients to build complex cytokine signalling networks underpinned by putative cytokine-cytokine interactions. The generated cytokine networks effectively captured known physiologically relevant cytokine-cytokine interactions which we recapitulated in vitro in UC patient-derived colonic epithelial organoids. These networks revealed new aspects of UC pathogenesis, including a cytokine subnetwork that is unique to treatment-naive UC patients, the identification of highly rewired cytokines across UC disease states (IL22, TL1A, IL23A, and OSM), JAK paralogue-specific cytokine-cytokine interactions, and the positioning of TL1A as an important upstream regulator of TNF and IL23A as well as an attractive therapeutic target. Overall, these findings open up several avenues for guiding future cytokine-targeting therapeutic approaches in UC, and the presented methodology can be readily applied to gain similar insights into other immune-mediated inflammatory diseases (IMIDs). One Sentence SummaryA systems immunology map of cytokine interaction networks in ulcerative colitis reveals novel insights into disease pathogenesis, with potential to guide future cytokine-targeting therapeutic strategies.

systems biology↗

bioRxiv2024

Fast-lived Vertebrate Hosts Exhibit Higher Potential for Mosquito-borne Parasite Transmission

The emergence of mosquito-borne zoonoses has continually increased over the past decade, posing a significant global public health challenge. Ecological theory can point to the characteristics of populations that make them more likely to form reservoirs of disease. The pace of life hypothesis posits that species with more rapid reproduction and shorter lifespans are more likely to be disease reservoirs than their slower-living cousins. Mathematical modeling suggests theoretical conditions under which this hypothesis is correct for directly- and environmentally-transmitted pathogens but its applicability to mosquito-borne disease systems has yet to be examined. We parameterized a mechanistic model with host trait data to investigate the link between the position of a species on the fast-slow life history continuum and the potential for it to spread mosquitoborne diseases. We evaluated the resulting relationships for four medically important mosquito species across their thermal niches and for four pathogens characterized by infection duration and the level of susceptibility of the focal host to infection. Finally, because the fast-slow life history continuum differs across taxonomic ranks, we considered the theory in the context of two orders of vertebrate hosts, Rodentia and Primates. After parameterizing our model, we found that, near universally across all the axes of variation considered, fast-lived hosts have higher transmission potential than slow-lived hosts. There was one exception: slower-lived hosts have higher transmission potential for parasites that cause long-enduring infections to which these hosts are highly susceptible. Generally, however, these connections hinge on the often unknown links between immunological traits, population density, and pace of life. Our analyses highlight immunological traits as a key knowledge gap with strong influence over the potential for transmission. Further investigation of the pace of life hypothesis will require a better understanding of how, for mosquito-borne parasitic infections, susceptibility and infection duration vary across the members of a taxonomic order.

ecology↗

bioRxiv2024

Genular: An Integrated Platform for Defining Cellular Identity and Function through Single-Cell Gene Expression and Multi-Domain Biological Data

Accurately defining cellular identity and function is essential for advancing immunology, understanding disease mechanisms, and developing targeted therapies. However, current bioinformatics tools are limited in their ability to integrate and analyze the vast and diverse single-cell RNA sequencing (scRNA-seq) datasets available, hindering the comprehensive capture of cellular heterogeneity and the identification of subtle genetic changes across immune states, differentiation pathways, and tissue contexts. To overcome these challenges, we introduce genular, an open-source platform that unifies gene expression data analysis across diverse cell types by integrating scRNA-seq data with extensive genomic and proteomic information from 16 databases, including NCBI Gene, Human Protein Atlas, STRING, and UniProt. genular aggregates data from more than 2,893 scRNA-seq experiments, encompassing over 74.5 million unique cells across various tissues and conditions. A key feature of genular is calculating a cell marker score for each gene, enabling the quantification of gene expression across cells to derive unique profiles specific to cell types, states, and lineages. Using genular, we differentiate T cell memory states, map differentiation profiles by tracking gene expression changes as monocytes mature into macrophages and lymphoid progenitor cells develop into T cells, and capture tissue-specific reprogramming of macrophages, revealing distinct gene expression profiles that enable specialized functions in different tissues. By integrating scRNA-seq data with multi-domain biological information and employing advanced statistical methodologies, genular provides a scalable platform that accurately defines cellular identities, functional states, and differentiation pathways. This comprehensive approach facilitates breakthroughs in immunology, gene regulation, cellular differentiation, and disease research, enabling a deeper understanding of immune cell functions and their roles in health and disease.

bioinformatics↗

bioRxiv2024

Tackling the Complexity of Spatial Transcriptomics Data Interpretation with Large Language Models

Spatial transcriptomics offers unprecedented insights into the complex cellular landscapes of tissues, particularly in cancer research where understanding the tumor microenvironment is crucial. However, interpreting the vast and intricate data generated by this technology remains a significant challenge. This study explores the potential of Large Language Models (LLMs) to assist in the analysis and interpretation of spatial transcriptomic data from a murine melanoma tumor model. We first evaluated the performance of multiple LLM models in describing and quantifying spatial gene expression patterns. Our benchmarking revealed that spatial transcriptomics data interpretation proved challenging for most models, with only a few demonstrating sufficient capability for this complex task. Using Claude 3.5 Sonnet, which showed the highest accuracy in spot quantification and pattern recognition, we developed a systematic workflow for analyzing the tumor immune landscape. The model first assisted in identifying and prioritizing panels of M1 and M2 macrophage-associated markers through knowledge-driven scoring. It then demonstrated remarkable ability to integrate spatial expression data with extensive immunological knowledge, providing sophisticated interpretation of local immune organization. When analyzing individual tumor regions, the model identified coordinated immunosuppressive mechanisms including metabolic barriers and disrupted pro-inflammatory signaling cascades, findings that both aligned with and extended current understanding of tumor immunology. This study highlights the potential of LLMs as powerful assistive tools in spatial transcriptomics analysis, capable of combining advanced pattern recognition with extensive knowledge integration to enhance data interpretation. While significant development work remains to make such workflows scalable, our proof of concept demonstrates that LLMs can help accelerate the translation of spatial transcriptomics data into biological insights.

cancer biology↗