UCLouvain - Royal Academy of Medicine of Belgium

Determination of Germ-Line Variations and Pathological Gene Expression that May Contribute to Immunopathology in COVID-19." The SARS-CoV-2 infection (1, 2), can be followed by a severe evolution with severe respiratory distress. We hypothesize that germline variants in genes involved in innate immunity, especially type I interferon induction and actions, predispose to delayed pathological response/cytokine storm. Our aims are to identify: i) such germ-line variants and ii) peripheral leukocyte gene expression that can predict unfavorable SARS-CoV2 infections. A group of SARS-CoV2 patients with unfavorable evolution, young and without co-morbidities (25) will be compared with an aged matched group of 25 SARS-CoV2 individuals with absence or a minimum of symptoms. Germ line DNA obtained from peripheral blood (PB) will be whole exome sequenced (WES) and analyzed with bioinformatics tools that are used for rare disease germline variations. PB RNA-sequencing will be used to call pathologic gene expression after reconstructing PB formula and comparing to actual blood counts. After Sanger sequencing confirmation, mutations will be validated in second cohorts that are in recruitment. Mutations will be tested functionally using hematopoietic cell lines and antiviral assays. "
Funding: application for Crédit urgent de recherche and funds from laboratory
Publication References: James C., Ugo V., Le Couedic J.P., Staerk J., Delhommeau F., Lacout C., Garcon L., Raslova H., Berger R., Bennaceur-Griscelli A., Villeval J.L., Constantinescu S.N., Casadevall N. & Vainchenker W. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 434(7037): 1144-1148, 2005. Defour J.P., Itaya M., Gryshkova V., Brett I.C., Pecquet C., Sato T., Smith S.O. & Constantinescu S.N. A tryptophan at the transmembrane-cytosolic junction modulates thrombopoietin receptor dimerization and activation. Proc. Natl. Acad. Sci. USA 110(7): 2540-5, 2013. Leroy E., Balligand T., Pecquet C., Mouton C., Colau D., Shiau A.K., Dusa A. & Constantinescu S.N. Differential effect of inhibitory strategies of the V617 mutant of JAK2 on cytokine receptor signaling. The Journal of Allergy and Clinical Immunology 144(1): 224-235, 2019. Kapralova K., Horvathova M., Pecquet C., Fialova Kucerova J., Pospisilova D., Leroy E., Kralova B., Milosevic Feenstra J.D., Schischlik F., Kralovics R., Constantinescu S.N. * & Divoky V. * Cooperation of germ line JAK2 mutations E846D and R1063H in hereditary erythrocytosis with megakaryocytic atypia. Blood 28(10): 1418-23, 2016. (*Corresponding authors). Mambet C., Babosova O., Defour J.P., Leroy E., Necula L., Stanca O., Tatic A., Berbec N., Coriu D., Belickova M., Kralova B., Lanikova L., Vesela J., Pecquet C., Saussoy P., Havelange V., Diaconu C.C., Divoky V. & Constantinescu S.N. Co-occurring JAK2 V617F and R1063H mutations increase JAK2 signaling and neutrophilia in MPN patients. Blood 132(25): 2695-2699, 2018. Constantinescu S.N., Croze E., Wang C., Murti A., Basu L., Mullersman J. & Pfeffer L.M. Role of the IFN-/ receptor chain 1 in structure and transmembrane signaling of the IFN  receptor complex. Proc. Natl. Acad. Sci. U.S.A. 91(20): 9602-9606, 1994 Labuhn M., Perkins K., Papaemmanuil E., Matzk S., Varghese L., Metzner M., Kennedy A., Amstislavskiy V., Risch T., Bhayadia R., Samulowski D., Garnett C., Cruz Hernandez D., Stoilova B., Iotchkova V., Scheer C., Yoshida K., Schwarzer A., Taub J., Crispino J.D., Weiss M.J., Hayashi A., Taga T., Ito E., Ogawa S., Reinhardt D., Yaspo M.L., Campbell P.J., Roberts I., Constantinescu S.N, Vyas P., Heckl D. & Klusmann J.H. Mechanisms of progression of myeloid preleukemia to transformed myeloid leukemia in children with down syndrome. Cancer Cell 36(2): 123-138, 2019
Contact: Prof. Stefan N. Constantinescu SIGN Unit, de Duve Institute and Ludwig Cancer Research Brussels Avenue Hippocrate 74, UCL 75-4 Brussels 1200 This email address is being protected from spambots. You need JavaScript enabled to view it. Prof. Jean-Philippe Defour Department of Clinical Biology, Cliniques universitaires Saint Luc Avenue Hippocrate 10 Brussels 1200 This email address is being protected from spambots. You need JavaScript enabled to view it.
Comment: This is a collaborative project with the following investigators: Jean-Philippe Defour,a,1 Hector Rodriguez-Villalobos,e,1, Benoît Kabamba-Mukadi,e,1, Jean Cyr Yombi,g,3, Pierre-François Laterre,f,2, Antoine Froidure,d,4, Nicolas Papadopoulos,a, Audrey Nedelec,a, Gabriela Oprea,h, Carmen C. Diaconu,i, Axelle Loriot,b, Laurent Gatto,b, Thomas Michiels,c, Stefan N. Constantinescu,a a Signal Transduction Pole, SIGN, de Duve Institute Brussels, Belgium b Computational biology and bioinformatics, CBIO, de Duve Institute , Brussels, Belgium c Virology, VIRO, de Duve Institute , Brussels, Belgium d Pôle de Pneumologie, PNEU, Institut de recherche expérimentale et Clinique, Brussels, Belgium e Pôle de Microbiologie médicale, MBLG, Institut de recherche expérimentale et Clinique, Brussels, Belgium f Pôle de Médecine Aiguë, MEDA, Institut de recherche expérimentale et Clinique g Pôle St. Luc, STLUC, Institut de recherche expérimentale et Clinique, Brussels, Belgium h Personal Genetics, Bucharest, Romania i Stefan S. Nicolau Institute of Virology, Romanian Academy, Bucharest, Romania 1 Department of Clinical Laboratory Medicine, Cliniques Universitaires Saint-Luc, Brussels, Belgium 2 Intensive Care Medicine, Cliniques Universitaires Saint-Luc, Brussels, Belgium 3 Department of Internal Medicine & Infectious Diseases, AIDS Reference Center, Cliniques Universitaires Saint-Luc, Brussels, Belgium 4 Department of Pneumology, Cliniques Universitaires Saint-Luc, Brussels, Belgium acronym of the project VARCOVID The project will continue past the first 25 patients with severe evolution and patients with mild evolution, as recruiting continues in several hospitals).