cometadata/datacite-titles-descriptions-related-identifiers huggingface dataset:
DOI: 10.5281/zenodo.5643550
title: Summary Statistics from "Meta-GWAS of PCSK9 levels detects two novel loci at APOB and TM6SF2"

description: GWAMA summary statistics of PCSK9 levels using fixed-effect model. Genome-wide data is given for Europeans with statin adjustment and Europeans without statin treatment only (subset of the population). In addition, locus-wide data of the PCSK9 gene locus for African-Americans without statin treatment is listed. When using this data, please cite: Pott J, Gadin J, Theusch E, et al.. Meta-GWAS of PCSK9 levels detects two novel loci at APOB and TM6SF2. Hum Mol Genet. 2021 Sep 30:ddab279. doi: 10.1093/hmg/ddab279. PMID: 34590679 All txt files contain the following columns: markername chr bp_hg19 (base position according to hg19) ea (effect allele) oa (other allele) eaf (effect allele frequency) info (minimal info score across all used studies) nSamples (sample size per SNP) nStudies (number of studies) beta (effect estimate) se (standard error) p (p-value) I2 (SNP heterogeneity across studies) phenotype (phenotyp setting)
description: Update: we added the sex-stratified summary statistics for the four genome-wide significant loci.
description: {"references": ["Pott J, Gadin J, Theusch E, Kleber ME, Delgado GE, Kirsten H, Hauck SM, Burkhardt R, Scharnagl H, Krauss RM, Loeffler M, M\u00e4rz W, Thiery J, Silveira A, Vant Hooft FM, Scholz M. Meta-GWAS of PCSK9 levels detects two novel loci at APOB and TM6SF2. Hum Mol Genet. 2021 Sep 30:ddab279. doi: 10.1093/hmg/ddab279"]}
DOI: 10.6084/m9.figshare.11769915.v3
title: Mutation on <i>lysX</i> from <i>Mycobacterium avium hominissuis</i> impacts the host–pathogen interaction and virulence phenotype

description: The <i>lysX</i> gene from <i>Mycobacterium avium hominissuis</i> (MAH) is not only involved in cationic antimicrobial resistance but also regulates metabolic activity. An MAH <i>lysX</i> deficient mutant was shown to exhibit a metabolic shift at the extracellular state preadapting the bacteria to the conditions inside host-cells. It further showed stronger growth in human monocytes. In the present study, the LysX activity on host–pathogen interactions were analyzed. The lysX mutant from MAH proved to be more sensitive toward host-mediated stresses such as reactive oxygen species. Further, the lysX mutant exhibited increased inflammatory response in PBMC and multinucleated giant cell (MGC) formation in human macrophages during infection studies. Coincidentally, the lysX mutant strain revealed to be more reproductive in the <i>Galleria mellonella</i> infection model. Together, these data demonstrate that LysX plays a role in regulating the bacillary load in host organisms and the lack of <i>lys</i><i>X</i> gene facilitates MAH adaptation to intracellular host-habitat, thereby suggesting an essential role of LysX in the modulation of host–pathogen interaction.
DOI: 10.6084/m9.figshare.13172679.v3
title: A new regulator in the crossroads of oxidative stress resistance and virulence in <i>Candida glabrata</i>: The transcription factor CgTog1

description: <i>Candida glabrata</i> is a prominent pathogenic yeast which exhibits a unique ability to survive the harsh environment of host immune cells. In this study, we describe the role of the transcription factor encoded by the gene <i>CAGL0F09229g</i>, here named CgTog1 after its <i>Saccharomyces cerevisiae</i> ortholog, as a new determinant of <i>C. glabrata</i> virulence. Interestingly, Tog1 is absent in the other clinically relevant <i>Candida</i> species (<i>C. albicans, C. parapsilosis, C. tropicalis, C. auris</i>), being exclusive to <i>C. glabrata</i>. CgTog1 was found to be required for oxidative stress resistance and for the modulation of reactive oxygen species inside <i>C. glabrata</i> cells. Also, CgTog1 was observed to be a nuclear protein, whose activity up-regulates the expression of 147 genes and represses 112 genes in <i>C. glabrata</i> cells exposed to H<sub>2</sub>O<sub>2</sub>, as revealed through RNA-seq-based transcriptomics analysis. Given the importance of oxidative stress response in the resistance to host immune cells, the effect of <i>CgTOG1</i> expression in yeast survival upon phagocytosis by <i>Galleria mellonella</i> hemocytes was evaluated, leading to the identification of CgTog1 as a determinant of yeast survival upon phagocytosis. Interestingly, CgTog1 targets include many whose expression changes in <i>C. glabrata</i> cells after engulfment by macrophages, including those involved in reprogrammed carbon metabolism, glyoxylate cycle and fatty acid degradation. In summary, CgTog1 is a new and specific regulator of virulence in <i>C. glabrata</i>, contributing to oxidative stress resistance and survival upon phagocytosis by host immune cells.
DOI: 10.6084/m9.figshare.11769915
title: Mutation on <i>lysX</i> from <i>Mycobacterium avium hominissuis</i> impacts the host–pathogen interaction and virulence phenotype

description: The <i>lysX</i> gene from <i>Mycobacterium avium hominissuis</i> (MAH) is not only involved in cationic antimicrobial resistance but also regulates metabolic activity. An MAH <i>lysX</i> deficient mutant was shown to exhibit a metabolic shift at the extracellular state preadapting the bacteria to the conditions inside host-cells. It further showed stronger growth in human monocytes. In the present study, the LysX activity on host–pathogen interactions were analyzed. The lysX mutant from MAH proved to be more sensitive toward host-mediated stresses such as reactive oxygen species. Further, the lysX mutant exhibited increased inflammatory response in PBMC and multinucleated giant cell (MGC) formation in human macrophages during infection studies. Coincidentally, the lysX mutant strain revealed to be more reproductive in the <i>Galleria mellonella</i> infection model. Together, these data demonstrate that LysX plays a role in regulating the bacillary load in host organisms and the lack of <i>lys</i><i>X</i> gene facilitates MAH adaptation to intracellular host-habitat, thereby suggesting an essential role of LysX in the modulation of host–pathogen interaction.
DOI: 10.6084/m9.figshare.12309824.v4
title: Relevance of inducible nitric oxide synthase for immune control of <i>Mycobacterium avium</i> subspecies <i>paratuberculosis</i> infection in mice

description: <b>Mycobacterium avium</b> subspecies <i>paratuberculosis</i> (MAP) causes Johne’s disease (JD), an incurable chronic intestinal bowel disease in ruminants. JD occurs worldwide and causes enormous economic burden in dairy industry. Research on JD pathobiology is hampered by its complexity which cannot completely be mimicked by small animal models. As a model the mouse allows dissecting some pathogenicity features of MAP. However, for unknown reasons MAP exhibits reduced growth in granulomas of infected mice compared to other <i>Mycobacterium avium</i> subspecies. Here, we characterized immune reactions of MAP-infected C57BL/6 mice. After infection, mice appeared fully immunocompetent. A strong antigen-specific T cell response was elicited indicated by IFNγ production of splenic T cells re-stimulated with MAP antigens. Function of splenic dendritic cells and proliferation of adoptively transferred antigen-specific CD4<sup>+</sup> T cells was unaltered. Isolated splenic myeloid cells from infected mice revealed that MAP resides in CD11b<sup>+</sup> macrophages. Importantly, sorted CD11b<sup>+</sup>CD11c<sup>−</sup> cells expressed high level of type 2 nitric oxide synthase (NOS2) but only low levels of pro- and anti-inflammatory cytokines. Correspondingly, MAP-infected MAC2 expressing myeloid cells in spleen and liver granuloma displayed strong expression of NOS2. In livers of infected <i>Nos2<sup>−/−</sup></i>mice higher bacterial loads, more granuloma and larger areas of tissue damage were observed 5 weeks post infection compared to wild type mice. <i>In vitro</i>, MAP was sensitive to NO released by a NO-donor. Thus, a strong T cell response and concomitant NOS2/NO activity appears to control MAP infection, but allows development of chronicity and pathogen persistence. A similar mechanism might explain persistence of MAP in ruminants.
DOI: 10.6084/m9.figshare.13172679
title: A new regulator in the crossroads of oxidative stress resistance and virulence in <i>Candida glabrata</i>: The transcription factor CgTog1

description: <i>Candida glabrata</i> is a prominent pathogenic yeast which exhibits a unique ability to survive the harsh environment of host immune cells. In this study, we describe the role of the transcription factor encoded by the gene <i>CAGL0F09229g</i>, here named CgTog1 after its <i>Saccharomyces cerevisiae</i> ortholog, as a new determinant of <i>C. glabrata</i> virulence. Interestingly, Tog1 is absent in the other clinically relevant <i>Candida</i> species (<i>C. albicans, C. parapsilosis, C. tropicalis, C. auris</i>), being exclusive to <i>C. glabrata</i>. CgTog1 was found to be required for oxidative stress resistance and for the modulation of reactive oxygen species inside <i>C. glabrata</i> cells. Also, CgTog1 was observed to be a nuclear protein, whose activity up-regulates the expression of 147 genes and represses 112 genes in <i>C. glabrata</i> cells exposed to H<sub>2</sub>O<sub>2</sub>, as revealed through RNA-seq-based transcriptomics analysis. Given the importance of oxidative stress response in the resistance to host immune cells, the effect of <i>CgTOG1</i> expression in yeast survival upon phagocytosis by <i>Galleria mellonella</i> hemocytes was evaluated, leading to the identification of CgTog1 as a determinant of yeast survival upon phagocytosis. Interestingly, CgTog1 targets include many whose expression changes in <i>C. glabrata</i> cells after engulfment by macrophages, including those involved in reprogrammed carbon metabolism, glyoxylate cycle and fatty acid degradation. In summary, CgTog1 is a new and specific regulator of virulence in <i>C. glabrata</i>, contributing to oxidative stress resistance and survival upon phagocytosis by host immune cells.
DOI: 10.6084/m9.figshare.12309824
title: Relevance of inducible nitric oxide synthase for immune control of <i>Mycobacterium avium</i> subspecies <i>paratuberculosis</i> infection in mice

description: <b>Mycobacterium avium</b> subspecies <i>paratuberculosis</i> (MAP) causes Johne’s disease (JD), an incurable chronic intestinal bowel disease in ruminants. JD occurs worldwide and causes enormous economic burden in dairy industry. Research on JD pathobiology is hampered by its complexity which cannot completely be mimicked by small animal models. As a model the mouse allows dissecting some pathogenicity features of MAP. However, for unknown reasons MAP exhibits reduced growth in granulomas of infected mice compared to other <i>Mycobacterium avium</i> subspecies. Here, we characterized immune reactions of MAP-infected C57BL/6 mice. After infection, mice appeared fully immunocompetent. A strong antigen-specific T cell response was elicited indicated by IFNγ production of splenic T cells re-stimulated with MAP antigens. Function of splenic dendritic cells and proliferation of adoptively transferred antigen-specific CD4<sup>+</sup> T cells was unaltered. Isolated splenic myeloid cells from infected mice revealed that MAP resides in CD11b<sup>+</sup> macrophages. Importantly, sorted CD11b<sup>+</sup>CD11c<sup>−</sup> cells expressed high level of type 2 nitric oxide synthase (NOS2) but only low levels of pro- and anti-inflammatory cytokines. Correspondingly, MAP-infected MAC2 expressing myeloid cells in spleen and liver granuloma displayed strong expression of NOS2. In livers of infected <i>Nos2<sup>−/−</sup></i>mice higher bacterial loads, more granuloma and larger areas of tissue damage were observed 5 weeks post infection compared to wild type mice. <i>In vitro</i>, MAP was sensitive to NO released by a NO-donor. Thus, a strong T cell response and concomitant NOS2/NO activity appears to control MAP infection, but allows development of chronicity and pathogen persistence. A similar mechanism might explain persistence of MAP in ruminants.
DOI: 10.6084/m9.figshare.12852036.v3
title: Transcriptional host–pathogen responses of <i>Pseudogymnoascus destructans</i> and three species of bats with white-nose syndrome

description: Understanding how context (e.g., host species, environmental conditions) drives disease susceptibility is an essential goal of disease ecology. We hypothesized that in bat white-nose syndrome (WNS), species-specific host–pathogen interactions may partly explain varying disease outcomes among host species. We characterized bat and pathogen transcriptomes in paired samples of lesion-positive and lesion-negative wing tissue from bats infected with <i>Pseudogymnoascus destructans</i> in three parallel experiments. The first two experiments analyzed samples collected from the susceptible Nearctic <i>Myotis lucifugus</i> and the less-susceptible Nearctic <i>Eptesicus fuscus</i>, following experimental infection and hibernation in captivity under controlled conditions. The third experiment applied the same analyses to paired samples from infected, free-ranging <i>Myotis myotis</i>, a less susceptible, Palearctic species, following natural infection and hibernation (n = 8 sample pairs/species). Gene expression by <i>P. destructans</i> was similar among the three host species despite varying environmental conditions among the three experiments and was similar within each host species between saprophytic contexts (superficial growth on wings) and pathogenic contexts (growth in lesions on the same wings). In contrast, we observed qualitative variation in host response: <i>M. lucifugus</i> and <i>M. myotis</i> exhibited systemic responses to infection, while <i>E. fuscus</i> up-regulated a remarkably localized response. Our results suggest potential phylogenetic determinants of response to WNS and can inform further studies of context-dependent host–pathogen interactions.
DOI: 10.6084/m9.figshare.12852036
title: Transcriptional host–pathogen responses of <i>Pseudogymnoascus destructans</i> and three species of bats with white-nose syndrome

description: Understanding how context (e.g., host species, environmental conditions) drives disease susceptibility is an essential goal of disease ecology. We hypothesized that in bat white-nose syndrome (WNS), species-specific host–pathogen interactions may partly explain varying disease outcomes among host species. We characterized bat and pathogen transcriptomes in paired samples of lesion-positive and lesion-negative wing tissue from bats infected with <i>Pseudogymnoascus destructans</i> in three parallel experiments. The first two experiments analyzed samples collected from the susceptible Nearctic <i>Myotis lucifugus</i> and the less-susceptible Nearctic <i>Eptesicus fuscus</i>, following experimental infection and hibernation in captivity under controlled conditions. The third experiment applied the same analyses to paired samples from infected, free-ranging <i>Myotis myotis</i>, a less susceptible, Palearctic species, following natural infection and hibernation (n = 8 sample pairs/species). Gene expression by <i>P. destructans</i> was similar among the three host species despite varying environmental conditions among the three experiments and was similar within each host species between saprophytic contexts (superficial growth on wings) and pathogenic contexts (growth in lesions on the same wings). In contrast, we observed qualitative variation in host response: <i>M. lucifugus</i> and <i>M. myotis</i> exhibited systemic responses to infection, while <i>E. fuscus</i> up-regulated a remarkably localized response. Our results suggest potential phylogenetic determinants of response to WNS and can inform further studies of context-dependent host–pathogen interactions.
DOI: 10.6084/m9.figshare.13359907.v3
title: Virulence role of the outer membrane protein CarO in carbapenem-resistant <i>Acinetobacter baumannii</i>

description: Novel approaches to treat carbapenem-resistant <i>Acinetobacter baumannii</i> (CRAB) infections are urgently needed and anti-virulence drugs represent promising alternatives, but our knowledge on potential targets is scarce. We searched for potential <i>A. baumannii</i> virulence factors by whole-genome sequencing-based comparisons of CRAB clinical isolates causing bloodstream infections secondary to ventilator-associated pneumonia from demographics and clinically homogeneous patients, who received optimal treatment but with different clinical outcomes. Thus, the <i>carO</i> gene was interrupted in CRAB isolates from surviving patients, while it was intact in isolates from non-surviving patients, and proteomic/immunoblot techniques corroborated it. When the virulence role of <i>A. baumannii</i> CarO was analyzed in model systems, isogenic Δ<i>carO</i> mutants and a CRAB clinical isolate with truncated CarO, showed lower ability to adhere and invade A549 cells and <i>in vivo</i> virulence. This unnoticed virulence role for CarO postulate this <i>A. baumannii</i> outer membrane protein as a potential target for new therapies against CRAB infections.
DOI: 10.6084/m9.figshare.12091419.v3
title: Direct interaction between RecA and a CheW-like protein is required for surface-associated motility, chemotaxis and the full virulence of <i>Acinetobacter baumannii</i> strain ATCC 17978

description: <i>Acinetobacter baumannii</i> is a nosocomial pathogen that causes multi-drug resistant infections mainly in immunocompromised patients. Although this gram-negative species lacks flagella, it is able to move over wet surfaces through a not well characterized type of movement known as surface-associated motility. In this study we demonstrate through the inactivation of the <i>A1S_2813</i> gene (coding a CheW-like protein) and <i>recA</i> (coding a DNA damage repair and recombination protein) that both genes are involved in the surface-associated motility and chemotaxis of <i>A. baumannii</i> ATCC 17978 strain. In addition, we also point out that the lack of either RecA or CheW-like proteins reduces its virulence in the <i>Caenorhabditis elegans</i> and the <i>Galleria mellonella</i> animal models. Furthermore, we show through co-immunoprecipitation assays that the CheW-like protein and RecA interact and that this interaction is abolished by the introduction of the mutation S97A in one of the domains of CheW-like protein that is structurally conserved in <i>Salmonella enterica</i> and necessary for the RecA-CheW interaction in this bacterial species. Finally, we show that the replacement of the wild-type CheW-like protein by that presenting the S97A mutation impairs surface-associated motility, chemotaxis and virulence of <i>A. baumannii</i> strain ATCC 17978.
DOI: 10.6084/m9.figshare.13359907
title: Virulence role of the outer membrane protein CarO in carbapenem-resistant <i>Acinetobacter baumannii</i>

description: Novel approaches to treat carbapenem-resistant <i>Acinetobacter baumannii</i> (CRAB) infections are urgently needed and anti-virulence drugs represent promising alternatives, but our knowledge on potential targets is scarce. We searched for potential <i>A. baumannii</i> virulence factors by whole-genome sequencing-based comparisons of CRAB clinical isolates causing bloodstream infections secondary to ventilator-associated pneumonia from demographics and clinically homogeneous patients, who received optimal treatment but with different clinical outcomes. Thus, the <i>carO</i> gene was interrupted in CRAB isolates from surviving patients, while it was intact in isolates from non-surviving patients, and proteomic/immunoblot techniques corroborated it. When the virulence role of <i>A. baumannii</i> CarO was analyzed in model systems, isogenic Δ<i>carO</i> mutants and a CRAB clinical isolate with truncated CarO, showed lower ability to adhere and invade A549 cells and <i>in vivo</i> virulence. This unnoticed virulence role for CarO postulate this <i>A. baumannii</i> outer membrane protein as a potential target for new therapies against CRAB infections.
DOI: 10.6084/m9.figshare.12091419
title: Direct interaction between RecA and a CheW-like protein is required for surface-associated motility, chemotaxis and the full virulence of <i>Acinetobacter baumannii</i> strain ATCC 17978

description: <i>Acinetobacter baumannii</i> is a nosocomial pathogen that causes multi-drug resistant infections mainly in immunocompromised patients. Although this gram-negative species lacks flagella, it is able to move over wet surfaces through a not well characterized type of movement known as surface-associated motility. In this study we demonstrate through the inactivation of the <i>A1S_2813</i> gene (coding a CheW-like protein) and <i>recA</i> (coding a DNA damage repair and recombination protein) that both genes are involved in the surface-associated motility and chemotaxis of <i>A. baumannii</i> ATCC 17978 strain. In addition, we also point out that the lack of either RecA or CheW-like proteins reduces its virulence in the <i>Caenorhabditis elegans</i> and the <i>Galleria mellonella</i> animal models. Furthermore, we show through co-immunoprecipitation assays that the CheW-like protein and RecA interact and that this interaction is abolished by the introduction of the mutation S97A in one of the domains of CheW-like protein that is structurally conserved in <i>Salmonella enterica</i> and necessary for the RecA-CheW interaction in this bacterial species. Finally, we show that the replacement of the wild-type CheW-like protein by that presenting the S97A mutation impairs surface-associated motility, chemotaxis and virulence of <i>A. baumannii</i> strain ATCC 17978.
DOI: 10.6084/m9.figshare.13003591
title: <i>Coxiella burnetii</i> replicates in <i>Galleria mellonella</i> hemocytes and transcriptome mapping reveals <i>in vivo</i> regulated genes

description: Larvae of the greater wax moth (<i>Galleria mellonella)</i> are susceptible to infection with <i>C. burnetii</i>, an obligate intracellular bacterial pathogen. We show that bacteria are found in hemocytes after infection, and occupy vacuoles which are morphologically similar to <i>Coxiella</i>-containing vacuoles seen in infected mammalian phagocytes. We characterized the infection by transcriptome profiling of bacteria isolated from the hemocytes of infected larvae and identified 46 highly upregulated genes. The encoded proteins are predicted to be involved in translation, LPS biosynthesis, biotin synthesis, scavenging of reactive oxygen species, and included a T4SS effector and 30 hypothetical proteins. Some of these genes had previously been shown to be upregulated in buffalo green monkey (BGM) cells or in mice, whilst others appear to be regulated in a host-specific manner. Altogether, our results demonstrate the value of the <i>G. mellonella</i> model to study intracellular growth and identify potential virulence factors of <i>C. burnetii</i>.
DOI: 10.6084/m9.figshare.13003591.v3
title: <i>Coxiella burnetii</i> replicates in <i>Galleria mellonella</i> hemocytes and transcriptome mapping reveals <i>in vivo</i> regulated genes

description: Larvae of the greater wax moth (<i>Galleria mellonella)</i> are susceptible to infection with <i>C. burnetii</i>, an obligate intracellular bacterial pathogen. We show that bacteria are found in hemocytes after infection, and occupy vacuoles which are morphologically similar to <i>Coxiella</i>-containing vacuoles seen in infected mammalian phagocytes. We characterized the infection by transcriptome profiling of bacteria isolated from the hemocytes of infected larvae and identified 46 highly upregulated genes. The encoded proteins are predicted to be involved in translation, LPS biosynthesis, biotin synthesis, scavenging of reactive oxygen species, and included a T4SS effector and 30 hypothetical proteins. Some of these genes had previously been shown to be upregulated in buffalo green monkey (BGM) cells or in mice, whilst others appear to be regulated in a host-specific manner. Altogether, our results demonstrate the value of the <i>G. mellonella</i> model to study intracellular growth and identify potential virulence factors of <i>C. burnetii</i>.