Biology subjects

Jacobs, A.

Publications and source records attributed to Jacobs, A..

27 records · Page 2Linked to original sources

bioRxiv2021

Induction of specific antibodies, IgG-secreting plasmablasts and memory B cells following BCG vaccination

Many tuberculosis (TB) vaccine candidates are designed as a boost to BCG; an understanding of the BCG-induced immune response is therefore critical, and the opportunity to relate this to circumstances where BCG does protect may direct the design of more efficacious vaccines. While the T cell response to BCG vaccination has been well-characterised, little is known about the B cell and antibody response. We demonstrate BCG vaccine-mediated induction of specific antibodies in different human populations and macaque species which represent important preclinical models for TB vaccine development. We observe a strong correlation between antibody titres in serum versus plasma with modestly higher titres in serum. We also report for the first time the rapid and transient induction of antibody-secreting plasmablasts following BCG vaccination, together with a robust and durable memory B cell response in humans. Finally, we demonstrate a potential contribution of the antibody response to BCG vaccine-mediated control of mycobacterial growth in vitro. Taken together, our findings indicate that the humoral immune response in the context of BCG vaccination merits further attention to determine whether TB vaccine candidates could benefit from the induction of humoral as well as cellular immunity.

immunology↗

bioRxiv2021

Single-Cell Proteomics Defines the Cellular Heterogeneity of Localized Prostate Cancer

Localized prostate cancer exhibits multiple genomic alterations and heterogeneity at the proteomic level. Single-cell technologies capture important cell-to-cell variability responsible for heterogeneity in biomarker expression that may be overlooked when molecular alterations are based on bulk tissue samples. The aim of this study was to identify novel prognostic biomarkers and describe the heterogeneity of prostate cancer and the associated immune cell infiltrates by simultaneously quantifying 36 proteins using single-cell mass cytometry analysis of over 1,6 million cells from 58 men with localized prostate cancer. To perform this task, we proposed a novel computational pipeline, Franken, which showed unprecedented combination of performance, sensitivity and scalability for high dimensional clustering compared to state of the art methods. We were able to describe subpopulations of immune, stromal, and prostate cells, including unique changes occurring in tumor tissues and high grade disease providing insights into the coordinated progression of prostate cancer. Our results further indicated that men with localized disease already harbor rare subpopulations that typically occur in castration-resistant and metastatic disease, which were confirmed through imaging. Our methodology could be used to discover novel prognostic biomarkers to personalize treatment and improve outcomes.

cancer biology↗

bioRxiv2020

Chromosome-level assembly of the Atlantic silverside genome reveals extreme levels of sequence diversity and structural genetic variation

The levels and distribution of standing genetic variation in a genome can provide a wealth of insights about the adaptive potential, demographic history, and genome structure of a population or species. As structural variants are increasingly associated with traits important for adaptation and speciation, investigating both sequence and structural variation is essential for wholly tapping this potential. Using a combination of shotgun sequencing, 10X Genomics linked reads and proximity-ligation data (Chicago and Hi-C), we produced and annotated a chromosome-level genome assembly for the Atlantic silverside (Menidia menidia) - an established ecological model for studying the phenotypic effects of natural and artificial selection - and examined patterns of genomic variation across two individuals sampled from different populations with divergent local adaptations. Levels of diversity varied substantially across each chromosome, consistently being highly elevated near the ends (presumably near telomeric regions) and dipping to near zero around putative centromeres. Overall, our estimate of the genome-wide average heterozygosity in the Atlantic silverside is the highest reported for a fish, or any vertebrate, to date (1.32-1.76% depending on inference method and sample). Furthermore, we also found extreme levels of structural variation, affecting ~23% of the total genome sequence, including multiple large inversions (> 1 Mb and up to 12.6 Mb) associated with previously identified haploblocks showing strong differentiation between locally adapted populations. These extreme levels of standing genetic variation are likely associated with large effective population sizes and may help explain the remarkable adaptive divergence among populations of the Atlantic silverside.

genomics↗

bioRxiv2020

A distinct innate immune signature marks progression from mild to severe COVID-19

Coronavirus disease 2019 (COVID-19) manifests with a range of severities, but immune signatures of mild and severe disease are still not fully understood. Excessive inflammation has been postulated to be a major factor in the pathogenesis of severe COVID-19 and innate immune mechanisms are likely to be central in the inflammatory response. We used 40-plex mass cytometry and targeted serum proteomics to profile innate immune cell populations from peripheral blood of patients with mild or severe COVID-19 and healthy controls. Sampling at different stages of COVID-19 allowed us to reconstruct a pseudo-temporal trajectory of the innate immune response. Despite the expected patient heterogeneity, we identified consistent changes during the course of the infection. A rapid and early surge of CD169+ monocytes associated with an IFN{gamma}+MCP-2+ signature quickly followed symptom onset; at symptom onset, patients with mild and severe COVID-19 had a similar signature, but over the course of the disease, the differences between patients with mild and severe disease increased. Later in the disease course, we observed a more pronounced re-appearance of intermediate/non-classical monocytes and mounting systemic CCL3 and CCL4 levels in patients with severe disease. Our data provide new insights into the dynamic nature of the early inflammatory response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and identifies sustained pathological innate immune responses as a likely key mechanism in severe COVID-19, further supporting investigation of targeted anti-inflammatory interventions in severe COVID-19.

immunology↗

bioRxiv2020

Lymphopenia-induced T cell proliferation is a hallmark of severe COVID-19

Coronavirus disease 2019 (COVID-19), caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has a broad clinical presentation ranging from asymptomatic infection to fatal disease. Different features associated with the immune response to SARS-CoV-2, such as hyperinflammation and reduction of peripheral CD8+ T cell counts are strongly associated with severe disease. Here, we confirm the reduction in peripheral CD8+ T cells both in relative and absolute terms and identify T cell apoptosis and migration into inflamed tissues as possible mechanisms driving peripheral T cell lymphopenia. Furthermore, we find evidence of elevated serum interleukin-7, thus indicating systemic T cell paucity and signs of increased T cell proliferation in patients with severe lymphopenia. Following T cell lymphopenia in our pseudo-longitudinal time course, we observed expansion and recovery of poly-specific antiviral T cells, thus arguing for lymphopenia-induced T cell proliferation. In summary, this study suggests that extensive T cell loss and subsequent T cell proliferation are characteristic of severe COVID-19.

immunology↗

bioRxiv2020

Alternative splicing and gene expression play contrasting roles in the parallel phenotypic evolution of a salmonid fish

Understanding the contribution of different molecular processes to the evolution and development of divergent phenotypes is crucial for identifying the molecular routes of rapid adaptation. Here, we used RNA-seq data to compare patterns of alternative splicing and differential gene expression in a case of parallel adaptive evolution, the replicated postglacial divergence of the salmonid fish Arctic charr (Salvelinus alpinus) into benthic and pelagic ecotypes across multiple independent lakes. We found that genes that were differentially spliced and differentially expressed between the benthic and pelagic ecotypes were mostly independent (<6% overlap) and were involved in different processes. Differentially spliced genes were primarily enriched for muscle development and functioning, while differentially expressed genes were mostly involved in energy metabolism, immunity and growth. Together, these likely explain different axes of divergence between ecotypes in swimming performance and activity. Furthermore, we found that alternative splicing and gene expression are mostly controlled by independent cis-regulatory quantitative trait loci (<3.4% overlap). Cis-regulatory regions were associated with the parallel divergence in splicing (16.5% of intron clusters) and expression (6.7 - 10.1% of differentially expressed genes), indicating shared regulatory variation across ecotype pairs. Contrary to theoretical expectation, we found that differentially spliced genes tended to be highly central in regulatory networks ( hub genes) and were annotated to significantly more gene ontology terms compared to non-differentially spliced genes, consistent with a higher level of connectivity and pleiotropy. Together, our results suggest that the concerted regulation of alternative splicing and differential gene expression through different regulatory regions leads to the divergence of complementary phenotypes important for local adaptation. This study provides novel insights into the importance of contrasting but putatively complementary molecular processes for rapid and parallel adaptive evolution.

evolutionary biology↗

bioRxiv2020

Repeated genomic signatures of adaptation to urbanisation in a songbird across Europe

Urbanisation is currently increasing worldwide, and there is now ample evidence of phenotypic changes in wild organisms in response to this novel environment, but the extent to which this adaptation is due to genetic changes is poorly understood. Current evidence for evolution is based on localised studies, and thus lacking replicability. Here, we genotyped great tits (Parus major) from nine cities across Europe, each paired with a rural site, and provide evidence of repeated polygenic responses to urban habitats. In addition, we show that selective sweeps occurred in response to urbanisation within the same genes across multiple cities. These genetic responses were mostly associated with genes related to neural function and development, demonstrating that genetic adaptation to urbanisation occurred around the same pathways in wildlife populations across a large geographical scale.

evolutionary biology↗

bioRxiv2018

Convergence in form and function overcomes non-parallel evolutionary histories in Arctic charr

Understanding the extent to which evolution is predictable under multifarious selection is a longstanding question in evolutionary biology. However, the interplay of stochastic and contingent factors influencing the extent of parallelism in nature is not well understood. To test the predictability of evolution, we studied a natural experiment on different organismal levels across lakes and evolutionary lineages of a freshwater salmonid fish, Arctic charr (Salvelinus alpinus). We identified significant phenotypic parallelism between Arctic charr ecotype pairs within a continuum of parallel evolution and highly parallel adaptive morphological traits. Variability in phenotypic predictability was explained by complex demographic histories, differing genomic backgrounds and genomic responses to selection, variable genetic associations with ecotype, and environmental variation. Remarkably, gene expression was highly similar across ecotype replicates, and explained the observed parallelism continuum. Our findings suggest that parallel evolution by non-parallel evolutionary routes is possible when the regulatory molecular phenotype compensates for divergent histories.

evolutionary biology↗

bioRxiv2017

Genetic fingerprinting of salmon louse (Lepeophtheirus salmonis) populations in the North-East Atlantic using a random forest classification approach

Caligid sea lice represent a significant threat to salmonid aquaculture worldwide. Lepeophtheirus salmonis is the predominant species that occurs in the Northern Hemisphere. Dispersal of sea lice between marine aquaculture sites and geographic regions is thought to occur rapidly via planktonic transport of larvae. Population genetic analyses have consistently shown minimal population genetic structure in North Atlantic L. salmonis, frustrating efforts to track louse populations, improve targeted control measures and understand local adaption to environmental conditions. The aim of this study was to test the power of reduced representation library sequencing (IIb-RAD sequencing) coupled with random forest machine learning algorithms to define markers for fine-scale discrimination of louse populations. We identified 1286 robustly supported SNPs among four L. salmonis populations from Ireland (N=2, 27 individuals), Scotland (N=1, 11 individuals) and North Norway (N=1, 12 individuals). Weak global structure (FSC = 0.018, p<0.0001) and only one significant pairwise FST comparison was observed (Scotland vs Kenmare Bay, (FST = 0.018, p<0.0001)) using all 1286 SNPs. The application of a random forest machine-learning algorithm identified 98 discriminatory SNPs that dramatically improved population assignment (DAPC assignment probability = 1), increased global Fsc = 0.098, (p<0.0001) and resulted in pairwise comparisons that all showed highly significant Fst-values (range = 0.081 - 0.096, p<0.0001). Out of 19 SNPs found to be under directional selection between populations, 12 corresponded to the discriminatory SNPs identified using random forest. Taken together our data suggest that L. salmonis SNP diversity exists with which it is possible to discriminate differences between nearby populations given suitable marker selection approaches, and that such differences might have an adaptive basis. We discuss these data in light of sea lice adaption to anthropogenic and environmental pressures as well as novel approaches to track and predict sea louse dispersal.

ecology↗