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RNA viruses and host factors

Karim Majzoub

Research projects

As obligate intracellular parasites, RNA viruses are normally restricted to their animal host, having established over long evolutionary periods intimate interactions with cellular host factors. In fact, RNA viruses rely heavily on host factors to complete their lifecycle during translation, transcription or replication of viral genomes. Viral interactions with cellular host factors largely determine the evolutionary success of a virus and the disease it may cause.  Deltaviruses being the smallest known viruses (by genome size) to infect animals, are the “quintessential” viruses, depending almost exclusively on host factors to complete their replication cycle. Using deltaviruses as simple RNA virus models, the aim of our group is to identify and characterize host factors essential for replication of RNA viruses in both human and animal hosts.

 For more than 40 years the only known member of deltaviruses was Hepatitis D Virus, a virus with no available antiviral cure, infecting 15 to 20 million individuals worldwide and leading to a very severe form of viral hepatitis and liver cancer. We have known for few years now that HDV-like viruses (referred to as deltaviruses) are present in a variety of animal vectors and reservoirs including bats, rats, snakes, birds, and insects.  Importantly, we now also know that deltaviruses are not restricted to the liver, as previously thought, and can replicate in a variety of animal tissues, possessing a previously unrecognized host shifting capacity. Our group is using and building new molecular tools to study and understand deltavirus infection in both human and animal hosts.

1- We are building new molecular tools to detect, track and visualize deltavirus genomes in human, rodent, snake, avian and insect cell culture models. These include cloning of novel deltavirus replicon and reporter systems coupled to novel microscopy methods to detect host and viral proteins and RNAs (e.g. nanobodies, SunTAG, RNA FISH).

2- We employ nucleic acid and protein purification methods coupled to proteomics (e.g. IP-MS, ChIRP-MS) to systematically evaluate Delta RNA-Host protein interactions in human, rodent, snake, avian and insect cell culture models. Our goal is to determine the protein and RNA-interactomes of complexes associated to animal deltaviruses, identifying universal, conserved and/or specific host factors that play roles in deltavirus replication and infection across the animal kingdom.

3- We use genetic screening approaches (e.g. CRIPSR knock-out, CRISPR activation) to identify, characterize and target pro-viral and antiviral factors controlling replication of HDV and animal deltaviruses in human cells. Our goal is to better understand the replication of these viruses in human cells and to generate a list of potential host targets for the development of new antiviral strategies.

HDV infected Huh7 cells

(RNA FISH HDV RNA, Immunostaining of HBV S protein)

List of publications :

Small RNAs are modified with N-glycans and displayed on the surface of living cells. Flynn RA, Pedram K, Malaker SA, Batista PJ, Smith BAH, Johnson AG, George BM, Majzoub K, Villalta PW, Carette JE, Bertozzi CR. Cell. 2021 Jun 10;184(12):3109-3124.e22. doi: 10.1016/j.cell.2021.04.023.

Improved Genome Editing through Inhibition of FANCM and Members of the BTR Dissolvase Complex. de Alencastro G, Puzzo F, Pavel-Dinu M, Zhang F, Pillay S, Majzoub K, et al. Molecular Therapy; 2021 Mar 3;29(3):1016-1027. doi: 10.1016.

Roadblocks and fast tracks: How RNA binding proteins affect the viral RNA journey in the cell.  Girardi E, Pfeffer S, Baumert TF, Majzoub K#. Seminars in Cell & Developmental Biology; 2021 Mar;111:86-100. doi: 10.1016/j.semcdb.2020.08.006. Review (# Corresponding author).

A genome-wide gain-of-function screen identifies CDKN2C as a HBV host factor. Eller C, Heydmann L, Colpitts C, El Saghire H, Piccioni F, Jühling F, Majzoub K et al. Nature Communications; 2020 Jun 1;11(1):2707. doi: 10.1038.

An RNA-centric dissection of host complexes controlling flavivirus infection. Ooi YS*, Majzoub K*, Flynn RA*, Mata MA, Diep J, Li JK, van Buuren N, Rumachik N, Johnson AG, Puschnik AS, Marceau CD, Mlera L, Grabowski JM, Kirkegaard K, Bloom ME, Sarnow P, Bertozzi CR, Carette JE. Nature Microbiology. 2019 Aug 5. doi: 10.1038/s41564-019-0518-2. (* Contributed equally/Co-first authors)

Hepatitis D Virus Infection Revisited. Verrier ER, Majzoub K, Baumert TF. Gastroenterology. 2019 Nov;157(5):1431-1432. doi: 10.1053/j.gastro.2019.09.029.

The Innate Antiviral Response in Animals: An Evolutionary Perspective from Flagellates to Humans.Majzoub K#, Wrensch F, Baumert TF#. Viruses. 2019 Aug 16;11(8).  pii: E758. doi:  0.3390/v11080758. Review. (#corresponding author).

Impact of a patient-derived hepatitis C viral RNA genome with a mutated microRNA binding site. Mata M, Neben S, Majzoub K, Carette J, Ramanathan M, Khavari PA, Sarnow P. PLoS Pathogens. 2019 May 10;15(5):e1007467. doi: 10.1371/journal.ppat.1007467.

Differential and convergent utilization of autophagy components by positive-strand RNA viruses. Abernathy E, Mateo R, Majzoub K, van Buuren N, Bird SW, Carette JE, Kirkegaard K. PLoS Biology. 2019 Jan 4;17(1):e2006926. doi: 10.1371/journal.pbio.2006926.

RNA-protein interaction detection in living cells. Ramanathan M, Majzoub K, Rao DS, Neela PH, Zarnegar BJ, Mondal S, Roth JG, Gai H, Kovalski JR, Siprashvili Z, Palmer TD, Carette JE, Khavari PA. Nature Methods. 2018 Mar;15(3):207-212. doi: 10.1038/nmeth.4601.

Fluorescently-tagged human eIF3 for single-molecule spectroscopy. Johnson AG, Petrov AN, Fuchs G, Majzoub K, Grosely R, Choi J, Puglisi JD. Nucleic Acids Research. 2018 Jan 25;46(2): e8. doi: 10.1093/nar/gkx1050.

A CRISPR toolbox to study virus-host interactions. Puschnik AS, Majzoub K, Ooi YS, Carette JE. Nature Reviews Microbiology. 2017 Jun;15(6):351-364. doi: 10.1038/nrmicro.2017.29. Review.

A Small-Molecule Oligosaccharyltransferase Inhibitor with Pan-flaviviral Activity.  Puschnik AS, Marceau CD, Ooi YS, Majzoub K, Rinis N, Contessa JN, Carette JE.  Cell Reports. 2017 Dec 12;21(11):3032-3039. doi: 10.1016/j.celrep.2017.11.054.

Definition of a RACK1 Interaction Network in Drosophila melanogaster Using SWATH-MS. Kuhn L*, Majzoub K*, Einhorn E, Chicher J, Pompon J, Imler JL, Hammann P, Meignin C. G3 Genes, Genomes, Genetics. 2017 Jul 5;7(7):2249-2258. doi: 10.1534/g3.117.042564. (* Contributed equally/ Co-first authors)

Genetic dissection of Flaviviridae host factors through genome-scale CRISPR screens. Marceau CD*, Puschnik AS*, Majzoub K, Ooi YS, Brewer SM, Fuchs G, Swaminathan K, Mata MA, Elias JE, Sarnow P, Carette JE. Nature. 2016 Jul 7;535(7610):159-63. (* Contributed equally/Co-first authors)

RNA interference to treat virus infections.  Majzoub K; Imler, J.L. Reviews in Cell Biology and Molecular Medicine; 2015 April.Wiley-VCH Verlag GmbH & Co. KGaA. DOI : 10.1002/3527600906. Book Chapter.

RACK1 controls IRES-mediated translation of viruses.Majzoub K, Hafirassou ML, Meignin C, Goto A, Marzi S, Fedorova A, Verdier Y, Vinh J, Hoffmann JA, Martin F, Baumert TF, Schuster C, Imler JL. Cell. 2014 Nov 20;159(5):1086-1095. doi: 10.1016/j.cell.2014.10.041.

A risk variant in an miR-125b binding site in BMPR1B is associated with breast cancer pathogenesis. Saetrom P, Biesinger J, Li SM, Smith D, Thomas LF, Majzoub K, Rivas GE, Alluin J, Rossi JJ, et al. Cancer Research. 2009 Sep 15;69(18):7459-65. doi: 10.1158/0008-5472.CAN-09-1201.

Recruitment

Recruitment announcements will be available soon.

If interested in the Lab’s research program and wish to join, please contact karim.majzoub@igmm.cnrs.fr

Members

Team leader

Karim MAJZOUB

Chercheur

+33 (0)4 34 35 9

Deborah GARCIA

AI-Recherche

+33 (0)4 34 35 96

102

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