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opencc-zeroJun 2021View details →

A common measure of prey immune function is not constrained by the cascading effects of predators

Simultaneously defending against predators, stymieing competitors, and generating immune responses can impose conflicting demands for host species caught in the entanglement of a food web. Host immunity is not only shaped by direct interactions among species, but also many indirect cascading effects. By reducing competition, predators in particular can affect resource acquisition necessary for hosts to mount energetically costly immune responses. However, identifying the links between predators and host immune responses determined by resource acquisition is a complex affair, because predators can (i) reduce host density and thus competition among hosts, (ii) exert non-consumptive trait-mediated effects on host resource acquisition behavior, and (iii) generate natural selection on host resource acquisition behavior. To examine the relative contributions of these potential predator driven density- and trait-mediated effects on a key aspect of immune function (total phenoloxidase activity, total PO), we conducted mesocosm and field experiments with larval damselflies ( Enallagma signatum ) and their dominant fish predator ( Lepomis macrochirus ). Although we expected to observe declines in total PO activity with increases in damselfly density, we found no relationship between density and total PO activity. We also found no support for the prediction that total PO activity would vary as a result of either non-consumptive trait-mediated effects or selection on damselfly foraging activity underlying resource acquisition. Despite the lack of trait- or densitymediated effects, we did find that total PO activity increased with damselfly prey density among lakes, implying resource limitation for this aspect of immune function. These unexpected results point to the need to better understand the ecological conditions whereby predators and competitors constrain immune functions necessary for species to defend themselves in complex food webs.

opencc-zeroJul 2021View details →

Macroevolutionary foundations of a recently-evolved innate immune defense (data)

Antagonistic interactions between hosts and parasites may drive the evolution of novel host defenses, or new parasite strategies. Host immunity is therefore one of the fastest evolving traits. But where do the novel immune traits come from? Here, we test for phylogenetic conservation in a rapidly evolving immune trait – peritoneal fibrosis. Peritoneal fibrosis is a costly defense against a specialist tapeworm, Schistocephalus solidus (Cestoda), expressed in some freshwater populations of threespine stickleback fish (Gasterosteus aculeatus, Perciformes). We asked whether stickleback fibrosis is a derived species-specific trait or an ancestral immune response that was widely distributed across ray-finned fish (Actinopterygii) only to be employed by threespine stickleback against the specialist parasite. We combined literature review on peritoneal fibrosis with a comparative experiment using either parasite-specific, or non-specific, immune challenge in deliberately selected species across fish tree of life. We show that ray-finned fish are broadly, but not universally, able to induce peritoneal fibrosis when challenged with a generic stimulus (Alum adjuvant). The experimental species were, however, largely indifferent to the tapeworm antigen homogenate. Peritoneal fibrosis, thus, appears to be a common and deeply conserved fish immune response that was co-opted by stickleback to adapt to a new selective challenge.

opencc-zeroAug 2021View details →

APOE4 is associated with elevated blood lipids and lower levels of innate immune biomarkers in a tropical Amerindian subsistence population

In post-industrial settings, APOE4 is associated with increased cardiovascular and neurological disease risk. However, the majority of human evolutionary history occurred in environments with higher pathogenic diversity and low cardiovascular risk. We hypothesize that in high-pathogen and energy-limited contexts, the APOE4 allele confers benefits by reducing innate inflammation when uninfected, while maintaining higher lipid levels that buffer costs of immune activation during infection. Among Tsimane forager-farmers of Bolivia (N=1266), APOE4 is associated with 30% lower C-reactive protein, and higher total cholesterol and oxidized-LDL. Blood lipids were either not associated, or negatively associated with inflammatory biomarkers, except for associations of oxidized-LDL and inflammation which were limited to high BMI adults. Further, APOE4 carriers maintain higher levels of total and LDL cholesterol at low BMIs. These results suggest the relationship between APOE4 and lipids may be beneficial for pathogen-driven immune responses, and unlikely to increase cardiovascular risk in an active subsistence population.

opencc-zeroAug 2021View details →

Innate immune activation by checkpoint inhibition in patient-derived lung cancer tissues

Although Pembrolizumab-based immunotherapy has significantly improved lung cancer patient survival, many patients show variable efficacy and resistance development. A better understanding of the drug's action is needed to improve patient outcomes. Functional heterogeneity of the tumor microenvironment (TME) is crucial to modulating drug resistance; understanding of individual patients' TME that impacts drug response is hampered by lack of appropriate models. Lung organotypic tissue slice cultures (OTC) with patients' native TME procured from primary and brain-metastasized (BM) non-small cell lung cancer (NSCLC) patients were treated with Pembrolizumab and/or beta-glucan (WGP, an innate immune activator). Metabolic tracing with 13C6-Glc/13C5,15N2-Gln, multiplex immunofluorescence (mIF), and digital spatial profiling (DSP) were employed to interrogate metabolic and functional responses to Pembrolizumab and/or WGP. Primary and BM PD-1+ lung cancer OTC responded to Pembrolizumab and Pembrolizumab + WGP treatments, respectively. Pembrolizumab activated innate immune metabolism and functions in primary OTC, which were accompanied by tissue damage. DSP analysis indicated an overall decrease in immunosuppressive macrophages and T cells but revealed microheterogeneity in immune responses and tissue damage. Two TMEs with altered cancer cell properties showed resistance. Pembrolizumab or WGP alone had negligible effects on BM-lung cancer OTC but Pembrolizumab + WGP blocked central metabolism with increased pro-inflammatory effector release and tissue damage. In depth metabolic analysis and multiplex TME imaging of lung cancer OTC demonstrated overall innate immune activation by Pembrolizumab but heterogeneous responses in the native TME of a patient with primary NSCLC. Metabolic and functional analysis also revealed synergistic action of Pembrolizumab and WGP in OTC of metastatic NSCLC.

openmit-licenseSep 2021View details →

16S processed data and shell processing scripts for "Epithelial-myeloid exchange of MHCII constrains immunity and microbiota composition"

Main repo for MHCII on IECs 16S processing code.

opencc-by-4.0Sep 2021View details →

Combined tumor and immune signals from genomes or transcriptomes predict outcomes of checkpoint inhibition in melanoma

Code and data for manuscript "Combined tumor and immune signals from genomes or transcriptomes predict outcomes of checkpoint inhibition in melanoma"

opencc-zeroOct 2021View details →

Relationships between immune gene expression and circulating cytokine levels in wild house mice

1. Quantitative PCR (qPCR) has been commonly used to measure gene expression in a number of research contexts, but the measured RNA concentrations do not always represent the concentrations of active proteins which they encode. This can be due to transcriptional regulation or post-translational modifications, or localisation of immune environments, as can occur during infection. However, in studies using free-living non-model species, such as in ecoimmunological research, qPCR may be the only available option to measure a parameter of interest, and so understanding the quantitative link between gene expression and associated effector protein levels is vital. 2. Here we use qPCR to measure concentrations of RNA from mesenteric lymph node (MLN) and spleen tissue, and multiplex ELISA of blood serum to measure circulating cytokine concentrations in a wild population of a model species, Mus musculus domesticus. 3. Few significant correlations were found between gene expression levels and circulating cytokines of the same immune genes or proteins, or related functional groups. Where significant correlations were observed, these were most frequently within the measured tissue (i.e. the expression levels of genes measured from spleen tissue were more likely to correlate with each other rather than with genes measured from MLN tissue, or with cytokine concentrations measured from blood). 4. Potential reasons for discrepancies between measures, including differences in decay rates and transcriptional regulation networks are discussed. We highlight the relative usefulness of different measures under different research questions, and consider what might be inferred from immune assays.

opencc-by-4.0Nov 2018View details →

Raw diffraction images of the type VI amidase immunity (Tai4) and the effector-immunity complex (Tae4-Tai4) from Agrobacterium tumefaciens

X-ray diffraction images of the type VI amidase immunity (Tai4) and the effector-immunity complex (Tae4-Tai4) crystals from Agrobacterium tumefaciens. This upload includes: <ul> <li>AtTai4 (PDB code: 6IJE) collected on BL41XU, SPring-8 using PILATUS3 6M detector. <ul> <li>0.5°/frame × 360 frames (helical data collection)</li> <li>P212121, a=53.92, b=57.76, c=71.47 Å</li> </ul> </li> <li>AtTae4-AtTai4 complex (PDB code: 6IJF) collected on BL32XU, SPring-8 using MX225-HS CCD detector. <ul> <li>0.5°/frame × 360 frames (helical data collection)</li> <li>P61, a=b=72.03, c=194.35 Å</li> </ul> </li> </ul>

opencc-zeroNov 2022View details →

Data for: Innate immune function and antioxidant capacity of nestlings of an African raptor co-vary with the level of urbanization around breeding territories

Urban areas provide breeding habitats for many species. However, animals raised in urban environments face challenges such as altered food availability and quality, pollution, and pathogens assemblages. These challenges can affect physiological processes like immune function and antioxidant defences which are important for fitness. Here, we explore how levels of urbanisation influence innate immune function, immune response to a mimicked bacterial infection and antioxidant capacity of nestling Black Sparrowhawks Accipiter melanoleucus in South Africa. We also explore the effect of timing of breeding and rainfall on physiology since both can influence the environmental condition under which nestlings are raised. Finally, because urbanisation can influence immune function indirectly, we use path analyses to explore direct and indirect associations between urbanisation, immune function, and oxidative stress. We obtained measures of innate immunity (haptoglobin, lysis, agglutination and bactericidal capacity), indices of antioxidant capacity (total non-enzymatic antioxidant capacity (tAOX), and total glutathione from nestlings from 2015 - 2019. In addition, in 2018 and 2019, we mimicked a bacterial infection by injecting nestlings with lipopolysaccharide and quantified their immune response. Increased urban cover was associated with an increase in lysis and a decrease in tAOX, but not with any of the other physiological parameters. Furthermore, except for agglutination, no physiological parameters were associated with the timing of breeding. Lysis and bactericidal capacity, however, varied consistently with the annual rainfall pattern. Immune response to a mimicked a bacterial infection decreased with urban cover but not with the timing of breeding nor rainfall. Our path analyses suggested indirect associations between urban cover and some immune indices via tAOX but not via the timing of breeding. Our results show that early-life development in an urban environment is associated with variation in immune and antioxidant functions. The direct association between urbanisation and antioxidant capacity and their impact on immune function is likely an important factor mediating the impact of urbanisation on urban-dwelling animals. Future studies should explore how these results are linked to fitness and whether the responses are adaptive for urban-dwelling species.

opencc-zeroNov 2022View details →

Barley endosomal MONENSIN SENSITIVITY1 is a target of the powdery mildew effector CSEP0162 and plays a role in plant immunity

Encasements formed around haustoria and biotrophic hyphae as well as hypersensitive reaction (HR) cell death are essential plant immune responses to filamentous pathogens. In this study we examine the components that may contribute to the absence of these responses in susceptible barley attacked by the powdery mildew fungus. We find that the effector CSEP0162 from this pathogen targets plant MONENSIN SENSITIVITY1 (MON1), which is important for the fusion of multivesicular bodies to their target membranes. Overexpression of CSEP0162 and silencing of barley MON1 both inhibit encasement formation. We find that the Arabidopsis ecotype No-0 has resistance to powdery mildew, and that this is partially dependent on MON1. Surprisingly, we find the MON1-dependent resistance in No-0 not only includes an encasement response, but also an effective HR. Similarly, silencing of MON1 in barley also blocks Mla3-mediated HR-based powdery mildew resistance. Our results indicate that MON1 is a vital plant immunity component, and we speculate that the barley powdery mildew fungus introduces the effector CSEP0162 to target MON1 and hence reduces encasement formation and HR.

opencc-zeroNov 2022View details →

Helminth-associated changes in host immune phenotype connect top-down and bottom-up interactions during co-infection

Within-host parasite interactions can be mediated by the host and changes in host phenotypes often serve as indicators of the presence or intensity of parasite interactions. Parasites like helminths induce a range of physiological, morphological, and immunological changes in hosts that can drive bottom-up (resource-mediated) or top-down (immune-mediated) interactions with co-infecting parasites. Although top-down and bottom-up interactions are typically studied in isolation, the diverse phenotypic changes induced by parasite infection may serve as a useful tool for understanding if, and when, these processes act in concert. Using an anthelmintic treatment study of African buffalo (Syncerus caffer), we tracked changes in host immunological and morphological phenotypes during helminth-coccidia co-infection to investigate their role in driving independent and combinatorial bottom-up and top-down parasite interactions. We also examined repercussions for host fitness. Clearance of a blood-sucking helminth, Haemonchus, from the host gastrointestinal tract induced a systemic Th2 immune phenotype, while clearance of a tissue-feeding helminth, Cooperia, induced a systemic Th1 phenotype. Furthermore, the Haemonchus-associated systemic Th2 immune phenotype drove simultaneous top-down and bottom-up effects that increased coccidia shedding by changing the immunological and morphological landscapes of the intestine. Higher coccidia shedding was associated with lower host body condition, a lower chance of pregnancy, and older age at first pregnancy, suggesting that coccidia infection imposed significant condition and reproductive costs on the host. Our findings suggest that top-down and bottom-up interactions may commonly co-occur and that tracking key host phenotypes that change in response to infection can help uncover complex pathways by which parasites interact.

opencc-by-4.0Dec 2022View details →

Immune selection determines tumor antigenicity and influences response to checkpoint inhibitors

R markdown files and source data to reproduce figures from the manuscript "Immune selection determines tumor antigenicity and influences response to checkpoint inhibitors"

Plant species with higher chemical defenses enhance herbivore cellular immunity with differential effectiveness against two parasitoid species

Insect herbivores simultaneously experience bottom-up effects of plant defensive chemistry and the top-down effects of natural enemies. At the intersection of these effects are herbivore immune systems, herbivore traits that have largely been overlooked in studies of plant-insect interactions. Most previous studies have demonstrated compromised immunity of herbivores that feed on plants with higher defensive chemistry. Many studies have used embedded microfilaments or silica beads as proxies for parasitoid eggs. Yet, parasitoids may evade or suppress host immune responses by injecting venom, calyx fluid, or through modifications of their egg surface structure, necessitating studies that include all three trophic levels to obtain a complete picture of how plant traits may modulate herbivore immunity.Here we examined the effect of host plant species that differ in glucosinolate (anti-herbivore compounds produced by plants in the Brassicaceae) concentrations on the immune status of an herbivore and its consequences for two species of parasitoids with different life history traits.We found that larvae of the butterfly Pieris rapae that fed on field mustard Brassica rapa, which contain 52-fold higher glucosinolate concentrations than collards B. oleracea, attained lower body weights and experienced prolonged development to adulthood.Yet, caterpillars that fed on B. rapa had enhanced cellular immunity, as measured by total and differential hemocyte counts, as well as melanization capacity compared to larvae that fed on B. oleracea.In turn, the likelihood that at least some eggs in clutches of the gregarious endoparasitoid Cotesia glomerata would be encapsulated, leading to a reduction in brood size, were three times greater when their host caterpillars fed on B. rapa compared to B. oleracea. Interestingly, eggs of the solitary endoparasitoid Cotesia rubecula were rarely encapsulated irrespective of the host plant on which their host caterpillar fed. Therefore, our results suggest that plant defense metabolites can influence the expression of herbivore immunity, but the effectiveness of this response strongly depends on the identity of the parasitoid and its ability to evade the caterpillar immune response, and possibly the evolution of these trophic interactions in non-native systems.

Not all roads lead to the immune system: The genetic basis of multiple sclerosis severity

Multiple sclerosis is a leading cause of neurological disability in adults. Heterogeneity in multiple sclerosis clinical presentation has posed a major challenge for identifying genetic variants associated with disease outcomes. To overcome this challenge, we used prospectively ascertained clinical outcomes data from the largest international multiple sclerosis Registry, MSBase. We assembled a cohort of deeply phenotyped individuals of European ancestry with relapse-onset multiple sclerosis. We used unbiased genome-wide association study and machine learning approaches to assess the genetic contribution to longitudinally defined multiple sclerosis severity phenotypes in 1,813 individuals. Our primary analyses did not identify any genetic variants of moderate to large effect sizes that met genome-wide significance thresholds. The strongest signal was associated with rs7289446 (β=-0.4882, P = 2.73 × 10−7), intronic to SEZ6L on chromosome 22. However, we demonstrate that clinical outcomes in relapse-onset multiple sclerosis are associated with multiple genetic loci of small effect sizes. Using a machine learning approach incorporating over 62,000 variants together with clinical and demographic variables available at multiple sclerosis disease onset, we could predict severity with an area under the receiver operator curve of 0.84 (95% CI 0.79–0.88). Our machine learning algorithm achieved positive predictive value for outcome assignation of 80% and negative predictive value of 88%. This outperformed our machine learning algorithm that contained clinical and demographic variables alone (area under the receiver operator curve 0.54, 95% CI 0.48–0.60). Secondary, sex-stratified analyses identified two genetic loci that met genome-wide significance thresholds. One in females (rs10967273; βfemale =0.8289, P = 3.52 × 10-8), the other in males (rs698805; βmale = -1.5395, P = 4.35 × 10-8), providing some evidence for sex dimorphism in multiple sclerosis severity. Tissue enrichment and pathway analyses identified an overrepresentation of genes expressed in central nervous system compartments generally, and specifically in the cerebellum (P = 0.023). These involved mitochondrial function, synaptic plasticity, oligodendroglial biology, cellular senescence, calcium and g-protein receptor signalling pathways. We further identified six variants with strong evidence for regulating clinical outcomes, the strongest signal again intronic to SEZ6L (adjusted hazard ratio 0.72, P = 4.85 × 10-4). Here we report a milestone in our progress towards understanding the clinical heterogeneity of multiple sclerosis outcomes, implicating functionally distinct mechanisms to multiple sclerosis risk. Importantly, we demonstrate that machine learning using common single nucleotide variant clusters, together with clinical variables readily available at diagnosis can improve prognostic capabilities at diagnosis, and with further validation has the potential to translate to meaningful clinical practice change.

Complex patterns shape immune genes diversity during invasion of common raccoon in Europe – selection in action despite genetic drift

Rapid adaptation is common in invasive populations and is crucial to their long-term success. The primary target of selection in the invasive species' new range is standing genetic variation. Therefore, genetic drift and natural selection acting on existing variation are key evolutionary processes through which invaders will evolve over a short timescale. In this study, we used the case of the raccoon Procyon lotor invasion in Europe to identify the forces shaping the diversity of immune genes during invasion. The genes involved in the defence against infection should be under intense selection pressure in the invasive range where novel pathogens are expected to occur. To disentangle the selective and demographic processes shaping the adaptive immune diversity of its invasive and expanding populations, we have developed species-specific SNP markers located in the coding regions of targeted immune-related genes. We characterised the genetic diversity of 110 functionally important immune genes in two invasive and one native raccoon genetic clusters, each presenting a different demographic history. Despite the strong effect of demographic processes in the invasive clusters, we detected a subset of genes exhibiting the diversity pattern suggestive of selection. The most likely process shaping the variation in those genes was balancing selection. The selected genes belong to toll-like receptors and cytokine-related genes. Our results suggest that the prevalence of selection depends on the level of diversity, i.e. – less genetically diverse invasive population from Czech Republic displayed fewer signs of selection. Our results highlight the role of standing genetic variation in adapting to a new environment. Understanding the evolutionary mechanisms behind invasion success would enable predicting how populations may respond to environmental change.

Impaired immune function accompanies social evolution in spiders

An efficient immune system is essential to the survival of many animals. Sociality increases risk of pathogen transmission, which should select for enhanced immune function. However, two hypotheses instead predict a weakened immune function: relaxed selection caused by social immunity/protection, and reduced efficacy of selection due to inbreeding, reproductive skew, and female bias in social species that reduces effective population size and accelerate genetic drift. We assessed the effect of social evolution on immune function in a comparative study of two social spider species and their closely related subsocial sister species (genus Stegodyphus). The haemolymph of social species was less efficient in inhibiting the growth of potentially pathogenic bacteria than that of subsocial species. Reduced efficacy of selection in social species was supported by comparative genomic analysis of immune genes showing substantially elevated non-synonymous substitutions in one of the social species. We propose that this impaired immune function is likely to be a result of reduced efficacy of selection because the evolution of sociality in spiders is accompanied by demographic processes that elevate genetic drift. There may also be positive feedback between pathogen-induced local extinctions and the resulting elevation of genetic drift which further weakens responses to selection by pathogens.

opencc-by-4.0Dec 2022View details →

Machine learning deconvolution of the immune response to dengue

Machine learning deconvolution of the immune response to dengue - dataset of antibody repertoire sequencing

opencc-zeroJan 2023View details →

Data from: Population connectivity patterns of genetic diversity, immune responses and exposure to infectious pneumonia in a metapopulation of desert bighorn sheep

Habitat fragmentation is an important driver of biodiversity loss and can be remediated through management actions aimed at maintenance of natural connectivity in metapopulations. Connectivity may protect populations from infectious diseases by preserving immunogenetic diversity and disease resistance. However, connectivity could exacerbate the risk of infectious disease spread across vulnerable populations. We tracked the spread of a novel strain of Mycoplasma ovipneumoniae in a metapopulation of desert bighorn sheep (Ovis canadensis nelsoni) in the Mojave desert to investigate how variation in connectivity among populations influenced disease outcomes. M. ovipneumoniae was detected throughout the metapopulation, indicating that the relative isolation of many of these populations did not protect them from pathogen invasion. However, we show that connectivity among bighorn sheep populations was correlated with higher immunogenetic diversity, a protective immune response and lower disease prevalence. Variation in protective immunity predicted infection risk in individual bighorn sheep and was associated with heterozygosity at genetic loci linked to adaptive and innate immune signalling. Together, these findings may indicate that population connectivity maintains immunogenetic diversity in bighorn sheep populations in this system and has direct effects on immune responses in individual bighorn sheep and their susceptibility to infection by a deadly pathogen. Our study suggests that the genetic benefits of population connectivity could outweigh the risk of infectious disease spread and supports conservation management that maintains natural connectivity in metapopulations.

opencc-by-4.0Jan 2023View details →

Immune selection determines tumor antigenicity and influences response to checkpoint inhibitors - Dataset

Dataset used from the publication "Tumor and Microenvironment Evolution during Immunotherapy with Nivolumab" published in  Cell. 2017 Nov 2;171(4):934-949.e16.  doi: 10.1016/j.cell.2017.09.028. Epub 2017 Oct 12.