The central aim of this axis is the development of new potent analgesics, building on the detailed elucidation of the AT2R-Traak model. To reach this aim the project involving 6 teams in France (Marsollier, Lebon, Sandoz, Boustié, Yeramian and Brodin) deploys a full-spectrum approach, from detailed molecular and cellular characterizations, to extensive exploratory screenings of natural compounds and in vivo pain assessments. The project is characterized by several promising strengths, as well as notable safeguards relative to the risks inherent to such approaches:
1) The effect of mycolactone appears to be very long lasting, thus comparing very favourably to compounds such as morphine, with the short duration of action being recognized as a severe shortcoming.
2) The system under study appears to be significantly more complex than other bioinspirational models for analgesia (for example scorpion toxins acting directly on ion channels), making the study more difficult, but offering from the applications perspective many different handles to interfere with the system.
3) The scientific approach adopted provides a sound safeguard relative to the medical objectives of the project, as the expected informations concerning the poorly characterized AT2R GPCR receptor and the Traak ionic channel will be valuable for their own sakes, notably in view of the increasing appreciation of the physiological importance of these components.
Priscille BRODIN, Contact
Mtb /macrophages/control of acidification / Tirap-CISH-vATPase
Stemming from our work , we will further characterize the complex formed by CISH and H+ V-ATPase at the vacuole through a higher spatial and temporal image-based approach. For the identification of other potential partners in the complex, we will perform a high throughput proteomic approach directly on Mtb containing phagosomes isolated from macrophages by immune-affinity separation. We will further
characterize the role of ubiquitination on the H+ V-ATPase. A more global approach aiming at deciphering the dual role of the host ubiquitinome at the Mtb containing vacuole will also be undertaken. Recently, we could also show that the TLR adaptor Tirap (also called MAL) is required for STAT5 phosphorylation and CISH expression, which suggests that Tirap is critical for CISH-mediated bacterial control. Strikingly, the inhibition of bacterial replication is strikingly more pronounced in Tirap-/- compared to Cish-/- macrophages and mice suggesting a unique role of Tirap, which will be further elucidated.
Small-molecules, antimicrobial peptides and combination of against intracellular Mtb
The drug discovery efforts and focus on chemical biology in Lille includes medical chemistry, high content screening capacity, target identification, nanoparticles drug delivery systems and in vivo validation should definitely continue to position us as key player in the field of therapeutics against TB. We will focus on drug candidates (either alone or in combination) having efficacy against Mtb replication within macrophages (also called antivirulence compounds or host-directed therapy). Our approaches will rely on i) the repurposing of commercially available drugs; and ii) the development of proprietary antimicrobial peptides (AMP) brought by Aurélie TASIEMSKI and François MASSOL joining the team in 2020. They identified a new antibiotic peptide, alvinellacin, from Alvinella pompejana, the emblematic worm that inhabits the hottest part of deep sea hydrothermal chimneys of the East Pacific Rise.This patented peptide (Aurélie Tasiemski et a lPatent number: 8652514 / Univ Lille) is the first active molecule against Mtb isolated from an extremophile animal and shows no homology to other molecules already described from terrestrial or marine organisms. The peptide folds into a double-stranded antiparallel β- sheet (β-hairpin motif) stabilized by two cysteine-bonds, which is unique to worms so far. Together with other molecules belonging to the same gene family and all issued from extremophile animals, their development against TB will be pursued using our efficient hit-to-lead optimisation pipeline. A. Tasiemski is invited to several oceanographic cruises giving access to extremophile organisms.
Aurelie TASIEMSKI, Contact
Risk of resistance development of novel TB drug candidates
Theoretical models of biological evolution will be developed to predict the conditions of emergence of Mtb resistance against the proposed treatments, using the modelling frameworks of quantitative genetics and adaptive dynamics (32, 33). The prediction model will be confronted to the results of selection of resistant strains during long-term exposure to sub-lethal doses of drugs on the Mtb infected macrophages. Different models will be designed to account for possible genetic correlations between tolerance and resistance and will incorporate different ingredients which can potentially enhance the acquisition of resistance in bacteria such as i) the capacity for tolerance against antibiotics (i.e. survival through a decrease in intracellular bacterial growth), ii) the type of interaction linking the immune system to pathogens with respect to host resources, iii) source-sink dynamics between reservoirs of pathogen resistance acquisition and immunitydeprived patients.
François MASSOL, Contact
De Manincor, N., Hautekèete, N., Piquot, Y, Schatz, B., Vanappelghem, C., & Massol, F. (2020) Does phenology explain plant-pollinator interactions at different latitudes? An assessment of its explanatory power in plant-hoverfly networks in French calcareous grasslands. Oikos, 129, 753-765.
Also available on Zenodo. 10.5281/zenodo.2543769, recommended by A. Eklöf (2019) The role of phenology for determining plant-pollinator interactions along a latitudinal gradient. PCI Ecology, 100034 10.24072/pci.ecology.100034
De Manincor, N., Hautekèete, N., Mazoyer, C., Moreau, P., Piquot, Y., Schatz, B., Schmitt, E., Zélazny, M., & Massol, F. (2020) How biased is our perception of plant-pollinator networks? A comparison of visit- and pollen-based representations of the same networks. Acta Oecologica, 105, 103551.
Fisogni, A., Hautekèete, N., Piquot, Y., Brun, M., Vanappelghem, C., Michez, D., & Massol, F. (2020) Urbanization drives an early spring for plants but not for pollinators. Oikos. 129, 1681-1691.
Jabot, F., Laroche, F., Massol, F., Arthaud, F., Crabot, J., Dubart, M., Blanchet, S., Munoz, F., David, P., & Datry, T. (2020) Assessing metacommunity processes through signatures in spatiotemporal turnover of community composition. Ecology Letters, 23, 1330-1339.
Also available on BioRxiv. 10.1101/480335, recommended by W. Ulrich (2019) On the importance of temporal meta-community dynamics for our understanding of assembly processes. PCI Ecology, 100027 10.24072/pci.ecology.100027
Macke, E., Callens, M., Massol, F., Vanoverberghe, I., De Meester, L., & Decaestecker, E. (2020) Diet and genotype of an aquatic invertebrate affect the composition of free-living microbial communities. Frontiers in Microbiology, 11. doi: 10.3389/fmicb.2020.00380
Makiola, A., Compson, Z. G., Baird, D. J., Barnes, M. A., Boerlijst, S. P., Bouchez, A., Brennan, G., Bush, A., Canard, E., Cordier, T., Creer, S., Curry, R. A., David, P., Dumbrell, A. J., Gravel, D., Hajibabaei, M., Hayden, B., van der Hoorn, B., Jarne, P., Jones, J. I., Karimi, B., Keck, F., Kelly, M., Knot, I. E., Krol, L., Massol, F., Monk, W. A., Murphy, J. F., Pawlowski, J., Poisot, T., Porter, T. M., Randall, K. C., Ransome, E., Ravigné, V., Raybould, A., Robin, S., Schrama, M., Schatz, B., Tamaddoni-Nezhad, A., Trimbos, K. B., Vacher, C., Vasselon, V., Wood, S. A., Woodward, G., & Bohan, D. A. (2020) Key questions for next-generation biomonitoring. Frontiers in Environmental Science, 7. doi: 10.3389/fenvs.2019.00197
Machelart, A., Willemart K, Zúñiga-Ripa A, Godard T, Plovier H, Wittmann C, Moriyón I, De Bolle X, Van Schaftingen E, Letesson JJ, Barbier T. Convergent evolution of zoonotic Brucella species toward the selective use of the pentose phosphate pathway. Proc Natl Acad Sci U S A. 2020 Oct 20;117(42):26374-26381. doi: 10.1073/pnas.2008939117.
Villemagne B, Machelart, A., Tran NC, Flipo M, Moune M, Leroux F, Piveteau C, Wohlkönig A, Wintjens R, Li X, Gref R, Brodin, P., Deprez B, Baulard AR, Willand N. Fragment-Based Optimized EthR Inhibitors with in Vivo Ethionamide Boosting Activity. ACS Infect Dis. 2020 Mar 13;6(3):366-378. doi: 10.1021/acsinfecdis.9b00277.
Iltis C, Moreau J, Gamb G, Manière C, Boidin Wichlacz C, Tasiemski A, Thiéry D, Louâpre P. Day/night variations of feeding and immune activities in larvae of the European grapevine moth, Lobesia botrana. Entomologia Generalis. 2021 Apr doi: 10.1127/entomologia/2021/1208
Bruno R, Zeppilli D, Boidin Wichlacz C, Sandulli R, Tasiemski A. Screening for antibacterial molecules in meiobenthic nematodes belonging to the Oncholaimidae family. Cah. Biol. Mar. 2020, 62 :DOI: 10.21411/CBM.A.D87636D
Le Bloa S, Boidin Wichlacz C, Cueff-Gauchard V, Rosa RD, Cuvillier-Hot V, Durand L, Methou P, Pradillon F, Cambon-Bonavita MA, Tasiemski A. Antimicrobial Peptides and Ectosymbiotic Relationships: Involvement of a Novel Type IIa Crustin in the Life Cycle of a Deep-Sea Vent Shrimp. Front Immunol.2020 Jul 13;11:1511. :10.3389/fimmu.2020.01511
Thomas F, Giraudeau M, Gouzerh F, Boutry J, Renaud F, Pujol P, Tasiemski A, Bernex F, Maraver A, Bousquet E, Dormont L, Osterkamp J, Roche B, Hamede R, Ujvari B, The evolution of resistance and tolerance as cancer defences.Parasitology; Cambridge Vol. 147, N° 3, 2020 Mar: 255-262. DOI:10.1017
Levillain F, Kim H, Woong Kwon K, Clark S, Cia F, Malaga W, Lanni F, Brodin P, Gicquel B, Guilhot C, Bancroft GJ, Williams A, Jae Shin S, Poquet Y, Neyrolles O. Preclinical assessment of a new live attenuated Mycobacterium tuberculosis Beijing-based vaccine for tuberculosis. Vaccine. 2020 Feb 5;38(6):1416-1423. doi: 10.1016/j.vaccine.2019.11.085
Moraski GC, Deboosère N, Marshall KL, Weaver HA, Vandeputte A, Hastings C, Woolhiser L, Lenaerts AJ, Brodin P, Miller MJ. Intracellular and in vivo evaluation of imidazo[2,1-b]thiazole-5-carboxamide anti-tuberculosis compounds. PLoS One. 2020 Jan 6;15(1):e0227224. doi: 10.1371/journal.pone.0227224
Brodin P.Cell Microbiol. 2021 Mar;23(3):e13288. Cell microbiology interview. doi: 10.1111/cmi.13288.
Orgeur M, Frigui W, Pawlik A, Clark S, Williams A, Ates LS, Ma L, Bouchier C, Parkhill J, Brodin P, Brosch R. Microb Genom. Pathogenomic analyses of Mycobacterium microti, an ESX-1-deleted member of the Mycobacterium tuberculosis complex causing disease in various hosts. 2021 Feb;7(2). doi: 10.1099/mgen.0.000505.
Boulinier T, Betoulle S, Caza F, St Pierre Y, Tornos J, Boidin Wichlacz C, Gamble A, Tasiemski. A. Panorama des recherches et des derniers résultats sur les pathogènes en milieu polaire, Approches complémentaires des interactions hôte-parasite en zones polaire: de la détection de parasites et agents infectieux à l'étude fonctionnelle, écologique et évolutive de leurs interactions avec leurs hôtes. Book chapter, Ipev 2020 Mar: rapport d'activité − campagne 2018 2019, 1246-7375, 6951, p 54-65
Belhaouane I, Hoffmann E, Chamaillard M, Brodin P, Machelart A. Paradoxical Roles of the MAL/Tirap Adaptor in Pathologies. Front Immunol. 2020 Sep 25;11:569127. doi: 10.3389/fimmu.2020.569127.
List of contracts
2021-2025 FEEDME Project funded by the ANR on “Feedbacks between epidemiology and evolution in spatially complex host-parasite metapopulations” (coordination: O. Kaltz, Partners : A. Tasiemski, F. Massol)
2021-2024 ASICS European Biodiversa project, funded in France by the ANR, on “Assessing and mitigating the effects of climate change and biological invasions on the spatial redistribution of biodiversity in cold environments” (coordination: D. Renault, Partners : A. Tasiemski, F. Massol)
2020-2022 RedAMPS Project funded by the SATT Nord on “Fighting human Respiratory Diseases with Anti-Microbial Peptides” (coordination: A. Tasiemski, 224k€)
2020 UFO IntraCIIL project involving 3 teams of the UMR on “Unmask potent biological Functions of reduced versus Oxydized cysteine rich peptides proposed as antibiotic agents against pulmonary infection” (coordination: A. Tasiemski, 15k€)
2020-2024 SubANTECO IPEV program, Project funded by the French Polar Institute (IPEV) that supports the cost of field missions (2 months/year for 4 years) in the French subantarctic Islands, Kerguelen and Crozet to collect and study polar invertebrates (coordination: D. Renault, 400k€, Partner: A. Tasiemski)
2020-2021 ANTI-CoV, ANR flash Covid-19, Title: Approche antivirale contre le coronavirus SARSCoV-2 (coordination: J. Dubuisson), (Participants: P. Brodin, A. Vandeputte, N. Deboosere)
2020-2021 SENOCOVID, ANR RA-Covid-19, Title: La sénescence cellulaire pulmonaire comme cible pour contrôler le COVID-19 (coordination: F. Trottein), (Participants: A. Machelart, E. Hoffmann)
2021-2025 SoftGlue, ANR-20-CE19-0020, Title: A soft glue to close wounds and relieve pain, Coordination: R. Gref (ISMO, CNRS); Partner IPL: F. Nesslany, P. Brodin, 113k€
2021-2026 MUSTART, ANR, PIA, Title: Multiparametric Strategies against Antibiotic Resistance in Tuberculosis, Coordination: A. Baulard (IPL); Partner: P Brodin, F Massol, 2,400k€
2021-2023 Anti-TB, CNRS, 80|PRIME, (coordination: R. Gref); Partner: P. Brodin