19 research outputs found

    Neutralization of the Plasmodium-encoded MIF ortholog confers protective immunity against malaria infection

    Get PDF
    Plasmodium species produce an ortholog of the cytokine macrophage migration inhibitory factor, PMIF, which modulates the host inflammatory response to malaria. Using a novel RNA replicon-based vaccine, we show the impact of PMIF immunoneutralization on the host response and observed improved control of liver and blood-stage Plasmodium infection, and complete protection from re-infection. Vaccination against PMIF delayed blood-stage patency after sporozoite infection, reduced the expression of the Th1-associated inflammatory markers TNF-alpha, IL-12, and IFN-gamma during blood-stage infection, augmented Tfh cell and germinal center responses, increased anti-Plasmodium antibody titers, and enhanced the differentiation of antigen-experienced memory CD4 T cells and liver-resident CD8 T cells. Protection from re-infection was recapitulated by the adoptive transfer of CD8 or CD4 T cells from PMIF RNA immunized hosts. Parasite MIF inhibition may be a useful approach to promote immunity to Plasmodium and potentially other parasite genera that produce MIF orthologous proteins

    Involvement of the Cytokine MIF in the Snail Host Immune Response to the Parasite Schistosoma mansoni

    Get PDF
    We have identified and characterized a Macrophage Migration Inhibitory Factor (MIF) family member in the Lophotrochozoan invertebrate, Biomphalaria glabrata, the snail intermediate host of the human blood fluke Schistosoma mansoni. In mammals, MIF is a widely expressed pleiotropic cytokine with potent pro-inflammatory properties that controls cell functions such as gene expression, proliferation or apoptosis. Here we show that the MIF protein from B. glabrata (BgMIF) is expressed in circulating immune defense cells (hemocytes) of the snail as well as in the B. glabrata embryonic (Bge) cell line that has hemocyte-like features. Recombinant BgMIF (rBgMIF) induced cell proliferation and inhibited NO-dependent p53-mediated apoptosis in Bge cells. Moreover, knock-down of BgMIF expression in Bge cells interfered with the in vitro encapsulation of S. mansoni sporocysts. Furthermore, the in vivo knock-down of BgMIF prevented the changes in circulating hemocyte populations that occur in response to an infection by S. mansoni miracidia and led to a significant increase in the parasite burden of the snails. These results provide the first functional evidence that a MIF ortholog is involved in an invertebrate immune response towards a parasitic infection and highlight the importance of cytokines in invertebrate-parasite interactions

    Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

    Get PDF
    Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

    Spatiotemporal Characteristics of the Largest HIV-1 CRF02_AG Outbreak in Spain: Evidence for Onward Transmissions

    Get PDF
    Background and Aim: The circulating recombinant form 02_AG (CRF02_AG) is the predominant clade among the human immunodeficiency virus type-1 (HIV-1) non-Bs with a prevalence of 5.97% (95% Confidence Interval-CI: 5.41–6.57%) across Spain. Our aim was to estimate the levels of regional clustering for CRF02_AG and the spatiotemporal characteristics of the largest CRF02_AG subepidemic in Spain.Methods: We studied 396 CRF02_AG sequences obtained from HIV-1 diagnosed patients during 2000–2014 from 10 autonomous communities of Spain. Phylogenetic analysis was performed on the 391 CRF02_AG sequences along with all globally sampled CRF02_AG sequences (N = 3,302) as references. Phylodynamic and phylogeographic analysis was performed to the largest CRF02_AG monophyletic cluster by a Bayesian method in BEAST v1.8.0 and by reconstructing ancestral states using the criterion of parsimony in Mesquite v3.4, respectively.Results: The HIV-1 CRF02_AG prevalence differed across Spanish autonomous communities we sampled from (p < 0.001). Phylogenetic analysis revealed that 52.7% of the CRF02_AG sequences formed 56 monophyletic clusters, with a range of 2–79 sequences. The CRF02_AG regional dispersal differed across Spain (p = 0.003), as suggested by monophyletic clustering. For the largest monophyletic cluster (subepidemic) (N = 79), 49.4% of the clustered sequences originated from Madrid, while most sequences (51.9%) had been obtained from men having sex with men (MSM). Molecular clock analysis suggested that the origin (tMRCA) of the CRF02_AG subepidemic was in 2002 (median estimate; 95% Highest Posterior Density-HPD interval: 1999–2004). Additionally, we found significant clustering within the CRF02_AG subepidemic according to the ethnic origin.Conclusion: CRF02_AG has been introduced as a result of multiple introductions in Spain, following regional dispersal in several cases. We showed that CRF02_AG transmissions were mostly due to regional dispersal in Spain. The hot-spot for the largest CRF02_AG regional subepidemic in Spain was in Madrid associated with MSM transmission risk group. The existence of subepidemics suggest that several spillovers occurred from Madrid to other areas. CRF02_AG sequences from Hispanics were clustered in a separate subclade suggesting no linkage between the local and Hispanic subepidemics

    Abstracts from the Food Allergy and Anaphylaxis Meeting 2016

    Get PDF

    RÎle de MIF (Macrophage Migration Inhibitory Factor) dans l'immunité innée et la réponse anti-schistosome chez Biomphalaria glabrata

    No full text
    We have identified and characterized a Macrophage Migration Inhibitory Factor (MIF) family member in the Lophotrochozoan invertebrate, Biomphalaria glabrata, the snail intermediate host of the human blood fluke Schistosoma mansoni. In mammals, MIF is a widely expressed pleiotropic cytokine with potent pro-inflammatory properties that controls cell functions such as gene expression, proliferation or apoptosis. Here we show that the MIF protein from B. glabrata (BgMIF) is expressed in circulating immune defense cells (hemocytes) of the snail as well as in the B. glabrata embryonic (Bge) cell line that has hemocyte-like features. Recombinant BgMIF (rBgMIF) induced cell proliferation and inhibited NO-dependent p53-mediated apoptosis in Bge cells. Moreover, knock-down of BgMIF expression in Bge cells interfered with the in vitro encapsulation of S. mansoni sporocysts. Finally, the in vivo knock-down of BgMIF prevented the changes in circulating hemocyte populations that occur in response to an infection by S. mansoni miracidia. These results provide the first functional evidence that a MIF ortholog is involved in an invertebrate immune response towards a parasitic infection and highlight the importance of cytokines in invertebrate-parasite interactions.Schistosoma mansoni est un parasite helminthe responsable de la schistosomiase intestinale, qui affecte 200 millions de personnes dans les zones tropicales et subtropicales, et l’on estime que 600 millions de personnes sont exposĂ©es au risque de cette infection. Le cycle de vie du parasite est complexe et il requiĂšre, un hĂŽte dĂ©finitif, l’homme et un hĂŽte intermĂ©diaire, un mollusque d’eau douce appelĂ© Biomphalaria glabrata. C’est chez le mollusque oĂč le parasite se multiplie de forme massive de lĂ  l’importance du mollusque dans la transmission du parasite Ă  l’homme. Lors de l’infection le mollusque met en place une rĂ©ponse cellulaire et humorale trĂšs marquĂ©es pouvant dans certains cas tuer le parasite. MalgrĂ© l’importance du mollusque, les mĂ©canismes molĂ©culaires qui gouvernent ces rĂ©ponses sont largement inconnus et donc l’étude de l’immunitĂ© du mollusque est une prioritĂ© en recherche mĂ©dicale. Nous avons identifiĂ© deux orthologues de la cytokine de mammifĂšre MIF (Macrophage Migration Inhibitory Factor ) BgMIF1 et BgMIF2. En utilisant des approches biochimiques et molĂ©culaires en combinaison avec la technique de RNAi in vitro et in vivo nous avons dĂ©montrĂ© le rĂŽle de BgMIF 1 et BgMIF2 comme rĂ©gulateurs centrales de l’immunitĂ© innĂ©e du mollusque. En particulaire BgMIF1 rĂ©gule l’activation des hĂ©mocytes et la rĂ©ponse d’encapsulation lors de l’infection. D’un autre cĂŽtĂ© BgMIF2 rĂ©gule dans la rĂ©ponse antibactĂ©rienne. Nos rĂ©sultats montrent que chez B. glabrata il y une rĂ©gulation fine de la rĂ©ponse immune innĂ©e et une capacitĂ© pour rĂ©pondre de façon diffĂ©rente lors d’un challenge immunitaire. De plus une rĂ©gulation par une cytokine de type vertĂ©brĂ© dans un invertĂ©brĂ© n’avait jusqu’à prĂ©sent jamais Ă©tĂ© dĂ©crite. Nos travaux Ă©tablissent les bases pour mieux comprendre les relations hĂŽte-parasite dans une maladie comme la schistosomiase, et aussi constituent une avancĂ©e importante du point de vue de l’évolution de l’immunitĂ© innĂ©e en gĂ©nĂ©ral.

    Role of MIF(Macrophage Migration Inhibitory Factor) in the innate immunity and anti-schistosome response in Biomphalaria glabrata

    No full text
    Schistosoma mansoni est un parasite helminthe responsable de la schistosomiase intestinale, qui affecte 200 millions de personnes dans les zones tropicales et subtropicales, et l’on estime que 600 millions de personnes sont exposĂ©es au risque de cette infection. Le cycle de vie du parasite est complexe et il requiĂšre, un hĂŽte dĂ©finitif, l’homme et un hĂŽte intermĂ©diaire, un mollusque d’eau douce appelĂ© Biomphalaria glabrata. C’est chez le mollusque oĂč le parasite se multiplie de forme massive de lĂ  l’importance du mollusque dans la transmission du parasite Ă  l’homme. Lors de l’infection le mollusque met en place une rĂ©ponse cellulaire et humorale trĂšs marquĂ©es pouvant dans certains cas tuer le parasite. MalgrĂ© l’importance du mollusque, les mĂ©canismes molĂ©culaires qui gouvernent ces rĂ©ponses sont largement inconnus et donc l’étude de l’immunitĂ© du mollusque est une prioritĂ© en recherche mĂ©dicale. Nous avons identifiĂ© deux orthologues de la cytokine de mammifĂšre MIF (Macrophage Migration Inhibitory Factor ) BgMIF1 et BgMIF2. En utilisant des approches biochimiques et molĂ©culaires en combinaison avec la technique de RNAi in vitro et in vivo nous avons dĂ©montrĂ© le rĂŽle de BgMIF 1 et BgMIF2 comme rĂ©gulateurs centrales de l’immunitĂ© innĂ©e du mollusque. En particulaire BgMIF1 rĂ©gule l’activation des hĂ©mocytes et la rĂ©ponse d’encapsulation lors de l’infection. D’un autre cĂŽtĂ© BgMIF2 rĂ©gule dans la rĂ©ponse antibactĂ©rienne. Nos rĂ©sultats montrent que chez B. glabrata il y une rĂ©gulation fine de la rĂ©ponse immune innĂ©e et une capacitĂ© pour rĂ©pondre de façon diffĂ©rente lors d’un challenge immunitaire. De plus une rĂ©gulation par une cytokine de type vertĂ©brĂ© dans un invertĂ©brĂ© n’avait jusqu’à prĂ©sent jamais Ă©tĂ© dĂ©crite. Nos travaux Ă©tablissent les bases pour mieux comprendre les relations hĂŽte-parasite dans une maladie comme la schistosomiase, et aussi constituent une avancĂ©e importante du point de vue de l’évolution de l’immunitĂ© innĂ©e en gĂ©nĂ©ral.lWe have identified and characterized a Macrophage Migration Inhibitory Factor (MIF) family member in the Lophotrochozoan invertebrate, Biomphalaria glabrata, the snail intermediate host of the human blood fluke Schistosoma mansoni. In mammals, MIF is a widely expressed pleiotropic cytokine with potent pro-inflammatory properties that controls cell functions such as gene expression, proliferation or apoptosis. Here we show that the MIF protein from B. glabrata (BgMIF) is expressed in circulating immune defense cells (hemocytes) of the snail as well as in the B. glabrata embryonic (Bge) cell line that has hemocyte-like features. Recombinant BgMIF (rBgMIF) induced cell proliferation and inhibited NO-dependent p53-mediated apoptosis in Bge cells. Moreover, knock-down of BgMIF expression in Bge cells interfered with the in vitro encapsulation of S. mansoni sporocysts. Finally, the in vivo knock-down of BgMIF prevented the changes in circulating hemocyte populations that occur in response to an infection by S. mansoni miracidia. These results provide the first functional evidence that a MIF ortholog is involved in an invertebrate immune response towards a parasitic infection and highlight the importance of cytokines in invertebrate-parasite interactions

    Virtual Screening and Optimization Yield Low-Nanomolar Inhibitors of the Tautomerase Activity of <i>Plasmodium falciparum</i> Macrophage Migration Inhibitory Factor

    No full text
    The <i>Plasmodium falciparum</i> orthologue of the human cytokine, macrophage migratory inhibitory factor (<i>Pf</i>MIF), is produced by the parasite during malaria infection and modulates the host’s immune response. As for other MIF orthologues, <i>Pf</i>MIF has tautomerase activity, whose inhibition may influence the cytokine activity. To identify small-molecule inhibitors of the tautomerase activity of <i>Pf</i>MIF, virtual screening has been performed by docking 2.1 million compounds into the enzymatic site. Assaying of 17 compounds identified four as active. Substructure search for the most potent of these compounds, a 4-phenoxypyridine analogue, identified four additional compounds that were purchased and also shown to be active. Thirty-one additional analogues were then designed, synthesized, and assayed. Three were found to be potent <i>Pf</i>MIF tautomerase inhibitors with <i>K</i><sub>i</sub> of ∌40 nM; they are also highly selective with <i>K</i><sub>i</sub> > 100 ÎŒM for human MIF
    corecore