Paired analysis of host and pathogen genomes identifies determinants of human tuberculosis
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PROVIDER: PRJNA1091619 | ENA |
REPOSITORIES: ENA
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Project description:The outcome of an infectious disease exposure is the result of interactions between host and pathogen and can depend on genetic variations in both. We explored this relationship in tuberculosis (TB) by conducting a genome-to-genome (g2g) study of paired human and Mycobacterium tuberculosis (Mtb) genomes from a cohort of 1556 TB patients in Lima, Peru. We identified an association between a human intronic variant (rs3130660, OR = 10.06, 95% CI: 4.87 - 20.77, P = 7.92 ⨉ 10-8 ) in the FLOT1 gene and a subclade of Mtb Lineage 2 (g2g-L2). We assessed this interaction in a Mtb-macrophage infection model between bacterial and host genetic backgrounds. We found that expression of FLOT1 and other genes in the MHC class-I region are differentially modulated by g2g-L2 compared to nearest neighbor strains. We also found distinct inflammatory responses with different host genetic backgrounds, with hosts carrying the A allele of rs3130660 inducing stronger type I and II interferon (IFN) gene signatures than hosts carrying only the T allele. TB infection with g2g-L2 strains shift macrophage responses away from this IFN signaling. In vitro analyses show that the g2g-L2 strains are distinguished by altered redox states and resistance to reductive stress and that these phenotypes result from a single mutation in thioredoxin reductase (trxB2, T2N). We also investigated this association in a 2020 cohort of 699 patients with TB recruited during the COVID-19 pandemic. Between 2010 and 2020, the prevalence of the g2g-L2 strain almost doubled, nearly fully replacing the other co-circulating L2 strains. However, g2g-L2 infection was not associated with rs3130660 in this cohort. These data raise the possibility of a more dynamic landscape of interacting host, pathogen and environmental risk factors than previously expected for TB.
2024-03-30 | GSE262379 | GEO
Project description:The factors that determine the outcome of clinical tuberculosis lie within both the host and the pathogen, Mycobacterium tuberculosis (Mtb). The advent of recombinant inbred mouse panels and next-generation transposon mutagenesis and sequencing approaches has enabled dissection of the host-pathogen interface for mammalian and pathogen genetic determinants of disease outcome. To identify host and pathogen genetic drivers of Mtb infection, we infected 19 genotypes from the BXD panel, bred from Mtb-resistant C57BL/6J (B6) and Mtb-susceptible DBA/2J (D2), with a comprehensive library of transposon mutants (TnSeq). The survival of each of the ~4000 bacterial mutants within each distinct host was quantified and leveraged as refined “endophenotypes”, directly reporting on the infection microenvironment. We leveraged QTL mapping to associate each varying bacterial fitness endophenotype to the host genome and identified 140 significant host-pathogen quantitative trait loci (hpQTL). This host-pathogen interaction screen reinforces the utility of bacterial mutant libraries as precise reporters of host immunological microenvironment during infection and highlights host gene candidates for further investigation.
2023-06-07 | GSE234093 | GEO
Project description:This work is an implementation science study that examines different aspects of implementing a single intervention. The intervention consists of asking community health centers to implement an outreach strategy to screen patients for colorectal cancer and for social determinants of health in community health centers at the same contact point. These are both clinical targets that the CHCs feel that their patients need and want to offer at a higher rate. The intervention consists of outreach to patients in need of colorectal cancer screening (CRC) to offer fecal immunochemical test (FIT) screening and screening for social determinants of health (SDOH). In this implementation science study, the intervention is an evidence-based intervention being implemented in real-world clinical practice. The intervention is the outreach to offer FIT and SDOH, conducted by clinic staff. Both evidence-based screening activities-FIT and SDOH screening-are used in the practices included in the study but pairing them is intended to increase efficiency and patient-centeredness by addressing health related social needs that may impact patients’ ability to engage in cancer screening. The study aims to test the effect of implementing the intervention on clinical and process outcomes. Clinical outcomes are CRC screening and SDOH screening. Analysis of process outcomes includes measuring what organizational factors influence implementation.
| 2354406 | ecrin-mdr-crc
Project description:Dual transcriptional profiling of host and bacteria during infection is challenging due to the low abundance of bacterial mRNA. We report Pathogen Hybrid Capture (PatH-Cap), a method to enrich for bacterial mRNA and deplete bacterial rRNA simultaneously from dual RNA-seq libraries using transcriptome-specific probes. By addressing both the differential RNA content of the host relative to the infecting bacterium and the overwhelming abundance of uninformative structural RNAs (rRNA, tRNA) of both species in a single step, this approach enables analysis of very low-input RNA samples. By sequencing libraries before (pre-PatH-Cap) and after (post-PatH-Cap) enrichment, we achieve dual transcriptional profiling of host and bacteria, respectively, from the same sample. Importantly, enrichment preserves relative transcript abundance and increases the number of unique bacterial transcripts per gene in post-PatH-Cap libraries compared to pre-PatH-Cap libraries at the same sequencing depth, thereby decreasing the sequencing depth required to fully capture the transcriptional profile of the infecting bacteria. We demonstrate that PatH-Cap enables the study of low-input samples including single eukaryotic cells infected by 1-3 Pseudomonas aeruginosa bacteria and paired host-pathogen temporal gene expression analysis of Mycobacterium tuberculosis infecting macrophages. PatH-Cap can be applied to the study of a range of pathogens and microbial species, and more generally, to lowly-abundant species in mixed populations.
| S-EPMC6917760 | biostudies-literature
Project description:The potential for epigenetic changes in host cells following microbial infection has been widely suggested, but few examples have been reported. We assessed genome-wide patterns of DNA methylation in human macrophage-like U937 cells following infection with Burkholderia pseudomallei, an intracellular bacterial pathogen and the causative agent of human melioidosis. Our analyses revealed significant changes in host cell DNA methylation, at multiple CpG sites in the host cell genome, following infection. Infection induced differentially methylated probes (iDMPs) showing the greatest changes in DNA methylation were found to be in the vicinity of genes involved in inflammatory responses, intracellular signalling, apoptosis and pathogen-induced signalling. A comparison of our data with reported methylome changes in cells infected with M. tuberculosis revealed commonality of differentially methylated genes, including genes involved in T cell responses (BCL11B, FOXO1, KIF13B, PAWR, SOX4, SYK), actin cytoskeleton organisation (ACTR3, CDC42BPA, DTNBP1, FERMT2, PRKCZ, RAC1), and cytokine production (FOXP1, IRF8, MR1). Overall our findings show that pathogenic-specific and pathogen-common changes in the methylome occur following infection.
2016-06-16 | GSE83379 | GEO
Project description:Host-pathogen co-evolutionary dynamics force microbial plant pathogens to constantly develop and adjust specific adaptations to thrive in their plant host, and therefore also act as strong drivers of divergence and speciation in pathogens. Factors that confer host specialization and determine host specificity are very diverse and range from molecular and morphological strategies to metabolic and reproductive adaptations. Identification of these key factors is a major goal in the study of pathogen evolution and may aid the development of sustainable crops and crop protection strategies. We here took a novel experimental approach and conducted comparative microscopy and transcriptome analyses of the closely related, recently diverged fungal pathogens Zymoseptoria tritici, Z. pseudotritici, and Z. ardabiliae that establish compatible and incompatible interactions with wheat. Although infections of the incompatible species induce plant defense response during invasion of stomatal openings, we found a highly conserved early-infection program among the three species. The transcriptional programs of the three pathogens are conserved to a large extent, as only 9.2% of the 8,885 orthologous genes are significantly differentially expressed during initial infection of wheat. The genes up-regulated in the compatible pathogen reflect adaptation to growth in wheat tissue e.g., by re-programming of fungal metabolism. In contrast, genes primarily involved in counteracting cell stress and damage are strongly induced in the incompatible species. Based on the species-specific gene expression profiles, we further identified nine candidate genes encoding putative effectors and host-specificity determinants in Z. tritici. These effectors are strongly induced in the compatible species and may interfere with host immune suppression. We also identify putative necrotrophic effectors which are induced at the onset of necrotrophic growth. Together, the results presented here indicate that host specialization has involved transcriptional adaptation of a relatively small number of genes. Our findings demonstrate the potential comparative analyses of compatible and incompatible infections present for identifying traits involved in pathogen evolution and host specialization.
2023-07-25 | GSE237842 | GEO
Project description:Host-pathogen genetic interactions underlie tuberculosis susceptibility in genetically diverse mice
| PRJNA689305 | ENA
Project description:The outcome of an encounter with Mycobacterium tuberculosis (Mtb) depends on the pathogen’s ability to adapt to the heterogeneous immune response of the host. Understanding this interplay has proven difficult, largely because experimentally tractable small animal models do not recapitulate the heterogenous disease observed in natural infections. We leveraged the genetically diverse Collaborative Cross (CC) mouse panel in conjunction with a library of Mtb mutants to associate bacterial genetic requirements with host genetics and immunity. We report that CC strains vary dramatically in their susceptibility to infection and represent reproducible models of qualitatively distinct immune states. Global analysis of Mtb mutant fitness across the CC panel revealed that a large fraction of the pathogen’s genome is necessary for adaptation to specific host microenvironments. Both immunological and bacterial traits were associated with genetic variants distributed across the mouse genome, elucidating the complex genetic landscape that underlies host-pathogen interactions in a diverse population.
2021-01-04 | GSE164156 | GEO
Project description:To advance our understanding of cellular host-pathogen interactions, technologies that facilitate the co-capture of both host and pathogen spatial transcriptome information are needed. Here, we present an approach to simultaneously capture host and pathogen spatial gene expression information from the same formalin-fixed paraffin embedded (FFPE) tissue section using the spatial transcriptomics technology. We applied the method to COVID-19 patient lung samples and enabled the dual detection of human and SARS-CoV-2 transcriptomes at 55 µm resolution. We validated our spatial detection of SARS-CoV-2 and identified an average specificity of 94.92% in comparison to RNAScope and 82.20% in comparison to in situ sequencing (ISS). COVID-19 tissues showed an upregulation of host immune response, such as increased expression of inflammatory cytokines, lymphocyte and fibroblast markers. Our colocalization analysis revealed that SARS-CoV-2+ spots presented shifts in host RNA metabolism, autophagy, NFκB, and interferon response pathways. Future applications of our approach will enable new insights into host response to pathogen infection through the simultaneous, unbiased detection of two transcriptomes.
| EGAS00001006186 | EGA