A New Family of Receptor Tyrosine Kinases with a Venus Flytrap Binding Domain in Insects and Other Invertebrates Activated by Aminoacids

Background: Tyrosine kinase receptors (RTKs) comprise a large family of membrane receptors that regulate various cellular processes in cell biology of diverse organisms. We previously described an atypical RTK in the platyhelminth parasite Schistosoma mansoni, composed of an extracellular Venus flytrap module (VFT) linked through a single transmembrane domain to an intracellular tyrosine kinase domain similar to that of the insulin receptor. Methods and Findings: Here we show that this receptor is a member of a new family of RTKs found in invertebrates, and particularly in insects. Sixteen new members of this family, named Venus Kinase Receptor (VKR), were identified in many insects. Structural and phylogenetic studies performed on VFT and TK domains showed that VKR sequences formed monophyletic groups, the VFT group being close to that of GABA receptors and the TK one being close to that of insulin receptors. We show that a recombinant VKR is able to autophosphorylate on tyrosine residues, and report that it can be activated by L-arginine. This is in agreement with the high degree of conservation of the alpha amino acid binding residues found in many amino acid binding VFTs. The presence of high levels of vkr transcripts in larval forms and in female gonads indicates a putative function of VKR in reproduction and/or development. Conclusion: The identification of RTKs specific for parasites and insect vectors raises new perspectives for the control of human parasitic and infectious diseases

Etude de l'adaptation de schistosoma mansoni à son environnement nutritif (rôles de la glutanime dans le métabolisme énergétique du sporocyste et analyse de la diversification de la famille des récepteurs de l'insuline chez le parasite)

La schistosomiase est un problème majeur de santé publique dans de nombreux pays émergents d Afrique, d Amérique latine et d Asie du sud Est, causant près de 300 000 décès par an. Cette maladie est due au schistosome qui est un ver parasite possédant un cycle de vie complexe durant lequel il passe par deux hôtes différents et six stades de développement distincts. Au cours de ma thèse je me suis penché sur la remarquable capcité d adaptation du parasite à ses hôtes successifs et notamment à l environnement nutritif qu il rencontre. Le sporocyste hébergé par l hôte intermédiaire mollusque, se trouve dans un milieu moins favorable que les stades évoluant dans les veines mésentériques riches en glucose, de l hôte vertébré. Nous avons pu montrer que la glutamine pouvait être une source d énergie alternative pour le sporocyste, ainsi qu un précurseur dans la voie de la glycéronéogénèse dépendante de la PEPCK. Cette voie métabolique qui n avait jusqu alors été observée que chez les mammifères, pourrait jouer un rôle important dans la physiologie du parasite. D autre part nous avons caractérisé chez S. mansoni, deux membres de la famille des récepteurs de l insuline (IR), connue pour être un régulateur clé du métabolisme énergétique chez les métazoaires. L étude des structures géniques et protéiques de SmIR-1 et SmIR-2 et leur capacité à lier la pro-insuline humaine, suggèrent fortement leur appartenance à la famille des IR. Cependant les différences du profil d expression de ces deux IR et les résultats de l analyse phylogénétique indiquent que SmIR-1 et SmIR-2 joueraient ds roôles distincts dans le développement du schistosome, contrastant ainsi avec la présence d un IR unique chez les autres invertébrés. Ces résultats suggèrent également l émergence et le maintient de SmIR-1 chez le schistosome afin d y exercer une fonction biologique spécifique ce que confirme des expériences d ARN interférence dans lesquels nous montrons l implication de ce récepteur dans la régulation de la prise de glucose, source d énergie majeure, par le parasiteLILLE2-BU Santé-Recherche (593502101) / SudocSudocFranceF

Mitochondrial Function in Peripheral Blood Mononuclear Cells (PBMC) Is Enhanced, Together with Increased Reactive Oxygen Species, in Severe Asthmatic Patients in Exacerbation

Asthma is a chronic inflammatory lung syndrome with an increasing prevalence and a rare but significant risk of death. Its pathophysiology is complex, and therefore we investigated at the systemic level a potential implication of oxidative stress and of peripheral blood mononuclear cells’ (PBMC) mitochondrial function. Twenty severe asthmatic patients with severe exacerbation (GINA 4–5) and 20 healthy volunteers participated at the study. Mitochondrial respiratory chain complexes activities using different substrates and reactive oxygen species (ROS) production were determined in both groups by high-resolution respirometry and electronic paramagnetic resonance, respectively. Healthy PBMC were also incubated with a pool of plasma of severe asthmatics or healthy controls. Mitochondrial respiratory chain complexes activity (+52.45%, p = 0.015 for VADP) and ROS production (+34.3%, p = 0.02) were increased in asthmatic patients. Increased ROS did not originate mainly from mitochondria. Plasma of severe asthmatics significantly increased healthy PBMC mitochondrial dioxygen consumption (+56.8%, p = 0.031). In conclusion, such asthma endotype, characterized by increased PMBCs mitochondrial oxidative capacity and ROS production likely related to a plasma constituent, may reflect activation of the immune system. Further studies are needed to determine whether increased PBMC mitochondrial respiration might have protective effects, opening thus new therapeutic approaches

SmPKC1, a new protein kinase C identified in the platyhelminth parasite Schistosoma mansoni

Schistosoma mansoni signal transduction pathways are promising sources of target molecules for the development of novel control strategies against this platyhelminth parasite of humans. Members of the protein kinase C (PKC) family play key roles in such pathways activated by both receptor tyrosine kinases and other receptors, controlling a variety of physiological processes. Here, we report the cloning and molecular characterization of the first PKC identified in S. mansoni. Structural analysis indicated that SmPKC1 exhibits all the features typical of the conventional PKC subfamily. the gene structure was determined in silico and found to comprise a total of 15 exons and 14 introns. This structure is highly conserved; all intron positions are also present in the human PKC beta gene and most of the exon sizes are identical. Using PCR on genomic DNA we were able to show that putative orthologues of SmPKC1 are present in 9 Schistosoma species. SmPKC1 expression is developmentally regulated with the highest level of transcripts in miracidia, whereas SmPKC1 protein expression is higher in the sporocyst. the localization of SmPKC1 on the sporocyst ridge cyton and in schistosomula acetabular glands suggests that the enzyme plays a role in signal transduction pathways associated with larval transformation. (c) 2006 Elsevier Inc. All rights reserved.Inst Pasteur, INSERM, U547, F-59019 Lille, FranceFiocruz MS, Ctr Pesquisas Rene Rachou, BR-30190002 Belo Horizonte, MG, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, Dept Microbiol Imunol & Parasitol, BR-04023900 São Paulo, BrazilNewcastle Univ, Sch Biol, Inst Res Environm & Sustainabil, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, EnglandSanta Casa Misericordia Belo Horizonte, Programa Pos Grad & Pesquisa, BR-30150221 Belo Horizonte, MG, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, Dept Microbiol Imunol & Parasitol, BR-04023900 São Paulo, BrazilWeb of Scienc

Validation of Strasbourg environmental exposure chamber (EEC) ALYATEC ® in mite allergic subjects with asthma

International audienc

SARS-CoV-2 Pneumonia in Hospitalized Asthmatic Patients Did Not Induce Severe Exacerbation

International audienceBackground: Viral infections are known to exacerbate asthma in adults. Previous studies have found few patients with asthma among severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia cases. However, the relationship between SARS-CoV-2 infection and severe asthma exacerbation is not known.Objective: To assess the frequency of asthma exacerbation in patients with asthma hospitalized for SARS-CoV-2 pneumonia and compare symptoms and laboratory and radiological findings in patients with and without asthma with SARS-CoV-2 pneumonia.Methods: We included 106 patients between March 4 and April 6, 2020, who were hospitalized in the Chest Diseases Department of Strasbourg University Hospital; 23 had asthma. To assess the patients' asthma status, 3 periods were defined: the last month before the onset of COVID-19 symptoms (p1), prehospitalization (p2), and during hospitalization (p3). Severe asthma exacerbations were defined according to Global INitiative for Asthma guidelines during p1 and p2. During p3, we defined severe asthma deterioration as the onset of breathlessness and wheezing requiring systemic corticosteroids and inhaled β2 agonist.Results: We found no significant difference between patients with and without asthma in terms of severity (length of stay, maximal oxygen flow needed, noninvasive ventilation requirement, and intensive care unit transfer); 52.2% of the patients with asthma had Global INitiative for Asthma step 1 asthma. One patient had a severe exacerbation during p1, 2 patients during p2, and 5 patients were treated with systemic corticosteroids and inhaled β2 agonist during p3.Conclusions: Our results demonstrate that patients with asthma appeared not to be at risk for severe SARS-CoV-2 pneumonia. Moreover, SARS-CoV-2 pneumonia did not induce severe asthma exacerbation

Characterization of Schistosoma mansoni Sds homologue, a leucine-rich repeat protein that interacts with protein phosphatase type 1 and interrupts a G(2)/M cell-cycle checkpoint

The suppressor of the dis2 mutant (sds22(+)) has been shown to be an essential regulator in cell division of fission and budding yeast where its deletion causes mitotic arrest. Its role seems to take place through the activation of PP1 (protein phosphatase type 1) in Schizosaccharomyces pombe. In the trematode Schistosoma mansoni, we have identified the Sds22 homologue (SmSds), and the PP1 (SmPP1). We showed by using a GST (glutathione S-transferase) pull-down assay that the SmSds gene product interacts with SmPP1 and that the SmSds–SmPP1 complex is present in parasite extracts. Furthermore, we observed that SmSds inhibited PP1 activity. Functional studies showed that the microinjection of SmSds into Xenopus oocytes interacted with the Xenopus PP1 and disrupted the G(2)/M cell-cycle checkpoint by promoting progression to GVBD (germinal vesicle breakdown). Similar results showing the appearance of GVBD were observed when oocytes were treated with anti-PP1 antibodies. Taken together, these observations suggest that SmSds can regulate the cell cycle by binding to PP1