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News Article | May 9, 2017
Site: phys.org

Resistance to malaria drugs means that pregnant women are unable to overcome the anaemia caused by the malaria parasite – and their babies are born undersized. A study carried out at Karolinska Institutet, however, exposes the effects of malaria in pregnant women and shows how the PTEF protein is central to the infection. The study, which is published in the scientific journal Nature Microbiology, opens the way for new malaria drugs. Some 50 million pregnant women contract malaria every year. The most common and most dangerous parasite, "Plasmodium falciparum", affects both female carriers of the malaria parasite and their unborn babies. The parasite retards fetal growth by consuming vital nutrients and the babies are born undersized. The women are also affected by anaemia when the parasite infects the placenta. When the parasite sends a 'glue protein' to the infected red blood membrane, tens, even hundreds of thousands of parasites can accumulate in the placental vessel wall and cause inflammation. First-time mothers, who have not built up immunity to the glue molecule, develop serious, chronic infections unless given prophylactic treatment. Due to growing resistance to modern malaria drugs, the treatments are not always that efficacious. The team behind the study found a certain protein in the parasite, PTEF, that is vital to the synthesis of the glue molecule to which the parasites attach themselves. The researchers show how PTEF binds direct to the cell's protein-manufacturing ribosome, where it speeds up the production of new glue molecules. "However, we can now stop this happening, and will one day be able to develop drugs that prevent the accumulation of parasites in the placenta," says Professor Mats Wahlgren at Karolinska Institutet's Department of Microbiology, Tumor and Cell Biology who was involved in the study. "We think that it will be possible in the future to deliver small molecules rather than traditional antibiotics to prevent pregnant women and the babies they are carrying from contracting malaria." The researchers also collaborated with Professor Suparna Sanyal at Uppsala University, who examined how the PTEF protein affected the ribosomes in E. coli bacteria models and found that it could stimulate protein synthesis in bacteria too. Explore further: Malaria parasites 'walk through walls' to infect humans More information: Sherwin Chan et al. Regulation of PfEMP1–VAR2CSA translation by a Plasmodium translation-enhancing factor, Nature Microbiology (2017). DOI: 10.1038/nmicrobiol.2017.68


Johansson D.X.,Tumor and Cell Biology | Krey T.,French National Center for Scientific Research | Andersson O.,Tumor and Cell Biology
Methods in Molecular Biology | Year: 2012

One of the major bottlenecks in antibody discovery for research and therapeutic applications is the need for large quantities of protein in a short amount of time. Here we describe an alternative method using the Drosophila melanogaster S2 expression system to produce high levels of antibodies (both IgG and Fab) with equivalent binding properties to antibodies produced in mammalian cell expression systems. Using the Drosophila S2 expression system for antibody production has many advantages over current mammalian systems making antibody expression, purification, and evaluation a much less time-consuming process. © 2012 Springer Science+Business Media, LLC.


Hoof I.,Technical University of Denmark | Hoof I.,University Utrecht | Perez C.L.,Tumor and Cell Biology | Perez C.L.,Swedish Institute for Infectious Disease Control | And 7 more authors.
Journal of Immunology | Year: 2010

HIV-1-specific CTL responses play a key role in limiting viral replication. CTL responses are sensitive to viral escape mutations, which influence recognition of the virus. Although CTLs have been shown to recognize epitope variants, the extent of this cross-reactivity has not been quantitatively investigated in a genetically diverse cohort of HIV-1-infected patients. Using a novel bioinformatic binding prediction method, we aimed to explain the pattern of epitope-specific CTL responses based on the patients' HLA genotype and autologous virus sequence quantitatively. Sequences covering predicted and tested HLA class I-restricted epitopes (peptides) within the HIV-Gag, Pol, and Nef regions were obtained from 26 study subjects resulting in 1492 patientspecific peptide pairs. Epitopes that were recognized in ELISPOT assays were found to be significantly more similar to the autologous virus than those that did not elicit a response. A single substitution in the presented epitope decreased the chance of a CTL response by 40%. The impact of sequence similarity on cross-recognition was confirmed by testing immune responses against multiple variants of six selected epitopes. Substitutions at central positions in the epitope were particularly likely to result in abrogation of recognition. In summary, the presented data demonstrate a highly restricted promiscuity of HIV-1-specific CTL in the recognition of variant epitopes. In addition, our results illustrate that bioinformatic prediction methods are useful to study the complex pattern of CTL responses exhibited by an HIV-1-infected patient cohort and for identification of optimal targets for novel therapeutic or vaccine approaches. Copyright © 2010 by The American Association of Immunologists, Inc.


Yakimchuk K.,Karolinska Institutet | Chen L.,Tumor and Cell Biology | Hasni M.S.,Karolinska Institutet | Okret S.,Karolinska Institutet | Jondal M.,Tumor and Cell Biology
Autoimmunity | Year: 2015

Glucocorticoids (GCs) strongly impact on different T cell subsets inducing generally immunosuppressive effects, whereas much less is known about the effect of GC on natural killer (NK) cells. The aims of this study were to investigate the effects of GC on T cell functions, including T cell-mediated anti-tumor immune response, and on NK cells. We have used lck-GR mice, which overexpress a transgenic rat GR in both T and NK cells. These mice were found to have decreased both CD4+ and CD8+ T cell populations in the periphery. In contrast, both NK and NKT cells were found in normal numbers in lck-GR mice. To identify genes and pathways affected by GR overexpression in our system in T cells, we have compared gene expression profiles in wild-type and lck-GR T cells. Among the genes upregulated in T cells from lck-GR mice, the microarray analysis has identified genes regulating expansion of regulatory T cells. The analysis of genes downregulated in lck-GR mice has identified genes and gene associated with the regulation of immune response. With regard to the effects on T cell functions in lck-GR mice, transgenic expression of GR had a suppressive effect on killer cell activity in vitro. In addition, lck-GR mice showed an increased tumor growth in murine tumor model in vivo, which may be a possible consequence of reduced T cell numbers and activity. We conclude that an increased expression of the GR strongly affects numbers and possibly functions of T cell subsets, but has little effect on NK cells. © 2014 Informa UK Ltd. All rights reserved.


Cagigi A.,Karolinska University Hospital | Palma P.,Ospedale Pediatrico Bambino Gesu | Palma P.,University of Rome Tor Vergata | Nilsson A.,University of Rome Tor Vergata | And 8 more authors.
AIDS | Year: 2010

Objective: To characterize the level of immature-transitional B-cells in blood during pediatric HIV-1 infection in relation to active or suppressed viremia. We also aimed at characterizing the level of expression of CXCR4, CXCR5 and CCR7 on immature-transitional B-cells, as these receptors are important mediators for homing of B-cells. DESIGN: Forty-eight HIV-1 vertically infected children (33 viral controllers and 15 viremic patients) and 33 age-matched healthy controls were enrolled in a cross-sectional study. Methods: We measured the levels of peripheral immature-transitional B-cells in all groups in relation to switched memory B-cells by flow cytometry. In parallel we evaluated CXCR4, CXCR5 and CCR7 expression on immature-transitional B-cells and measured plasma levels of CXCL12, BAFF and interleukin-7 by ELISA. Results: We observed a lack of physiological age-related decline of immature-transitional B-cells in viremic children in parallel to a decreased level of switched memory B-cells. Interestingly, immature-transitional B-cells from viremic children presented with high levels of CXCR4. On the contrary, the level of CXCL12, the natural ligand for CXCR4, was lowest in the HIV-1 infected group, as compared with controls. Conclusion: Control of HIV-1 viremia through antiretroviral treatment appears to be crucial in decreasing the expansion and alteration of immature-transitional B-cells. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.


PubMed | Aix - Marseille University, University of Khartoum and Tumor and Cell Biology
Type: Journal Article | Journal: Standards in genomic sciences | Year: 2014

Staphylococcus aureus subsp. anaerobius is responsible for Morels disease in animals and a cause of abscess in humans. It is characterized by a microaerophilic growth, contrary to the other strains of S. aureus. The 2,604,446-bp genome (32.7% GC content) of S. anaerobius ST1464 comprises one chromosome and no plasmids. The chromosome contains 2,660 open reading frames (ORFs), 49 tRNAs and three complete rRNAs, forming one complete operon. The size of ORFs ranges between 100 to 4,600 bp except for two ORFs of 6,417 and 7,173 bp encoding segregation ATPase and non-ribosomal peptide synthase, respectively. The chromosome harbors Staphylococcus phage 2638A genome and incomplete Staphylococcus phage genome PT1028, but no detectable CRISPRS. The antibiotic resistance gene for tetracycline was found although Staphylococcus aureus subsp. anaerobius is susceptible to tetracycline in-vitro. Intact oxygen detoxification genes encode superoxide dismutase and cytochrome quinol oxidase whereas the catalase gene is impaired by a stop codon. Based on the genome, in-silico multilocus sequence typing indicates that S. aureus subsp. anaerobius emerged as a clone separated from all other S. aureus strains, illustrating host-adaptation linked to missing functions. Availability of S. aureus subsp. anaerobius genome could prompt the development of post-genomic tools for its rapid discrimination from S. aureus.


Chen X.,Tumor and Cell Biology | Yammine S.,Tumor and Cell Biology | Shi C.,Tumor and Cell Biology | Tark-Dame M.,University of Amsterdam | And 2 more authors.
Epigenetics | Year: 2014

Despite considerable efforts, our understanding of the organization of higher order chromatin conformations in single cells and how these relate to chromatin marks remains poor. We have earlier invented the Chromatin In Situ Proximity (ChrISP) technique to determine proximities between chromatin fibers within a single chromosome. Here we used ChrISP to identify chromosome 11-specific hubs that are enriched in the H3K9me2 mark and that project toward the nuclear membrane in finger-like structures. Conversely, chromosome 11-specfic chromatin hubs, visualized by the presence of either H3K9me1 or H3K9me3 marks, are chromosome-wide and largely absent at the nuclear periphery. As the nuclear periphery-specific chromatin hubs were lost in the induced reduction of H3K9me2 levels, they likely represent Large Organization Chromatin in Lysine Methylation (LOCK) domains, previously identified by ChIP-seq analysis. Strikingly, the downregulation of the H3K9me2/3 marks also led to the chromosome-wide compaction of chromosome 11, suggesting a pleiotropic function of these features not recognized before. The ChrISP-mediated visualization of dynamic chromatin states in single cells thus provides an analysis of chromatin structures with a resolution far exceeding that of any other light microscopic technique. © 2014 Taylor & Francis Group, LLC.


Joffre E.,Sahlgrenska Academy | Sjoling A.,Tumor and Cell Biology
Gut Microbes | Year: 2016

The heat-labile toxin (LT) is one of the major virulence factors of enterotoxigenic Escherichia coli (ETEC). We recently described that 20 polymorphic LT variants are present in ETEC strains isolated globally. Two of the variants, LT1 and LT2, are particularly common and we found that they were associated with clonal ETEC lineages that express the colonization factors (CFs), CFA/I, CS1+CS3, CS2+CS3, and CS5+CS6. ETEC expressing these CFs are frequently found among ETEC strains isolated from cases with diarrhea. ETEC expressing the colonization factors CS1+CS3, and CS2+CS3 are found in 2 discrete clonal lineages and express the LT1 variant and heat stable toxin (STh). Although they clearly are virulent they neither produce, nor secrete, high amounts of LT toxin. On the other hand ETEC strains expressing LT, STh, CFA/I and LT, STh, CS5+CS6, carry the LT2 variant and produce and secrete significantly more LT toxin. Despite differences in toxin production, LT1 and LT2 are found in ETEC lineages that have managed to spread globally confirming that these variants are important for ETEC virulence. © 2016 The Author(s). Published with license by Taylor & Francis Group, LLC.


PubMed | Tumor and Cell Biology
Type: | Journal: Methods in molecular biology (Clifton, N.J.) | Year: 2012

One of the major bottlenecks in antibody discovery for research and therapeutic applications is the need for large quantities of protein in a short amount of time. Here we describe an alternative method using the Drosophila melanogaster S2 expression system to produce high levels of antibodies (both IgG and Fab) with equivalent binding properties to antibodies produced in mammalian cell expression systems. Using the Drosophila S2 expression system for antibody production has many advantages over current mammalian systems making antibody expression, purification, and evaluation a much less time-consuming process.


PubMed | Tumor and Cell Biology.
Type: Journal Article | Journal: The Journal of infectious diseases | Year: 2014

Pneumococcal serotypes are represented by a varying number of clonal lineages with different genetic contents, potentially affecting invasiveness. However, genetic variation within the same genetic lineage may be larger than anticipated.A total of 715 invasive and carriage isolates from children in the same region and during the same period were compared using pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing. Bacterial genome sequencing, functional assays, and in vivo virulence mice studies were performed.Clonal types of the same serotype but also intraclonal variants within clonal complexes (CCs) showed differences in invasive-disease potential. CC138, a common CC, was divided into several PFGE patterns, partly explained by number, location, and type of temperate bacteriophages. Whole-genome sequencing of 4 CC138 isolates representing PFGE clones with different invasive-disease potentials revealed intraclonal sequence variations of the virulence-associated proteins pneumococcal surface protein A (PspA) and pneumococcal choline-binding protein C (PspC). A carrier isolate lacking PcpA exhibited decreased virulence in mice, and there was a differential binding of human factor H, depending on invasiveness.Pneumococcal clonal types but also intraclonal variants exhibited different invasive-disease potentials in children. Intraclonal variants, reflecting different prophage contents, showed differences in major surface antigens. This suggests ongoing immune selection, such as that due to PspC-mediated complement resistance through varied human factor H binding, that may affect invasiveness in children.

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