dimnp

Post-translational regulation of proteins and bacterial pathogenicity
 
Team manager: Virginie Molle (DR CNRS)
 
 20170523 100542 2
 

Team

BLANC-POTARD Anne

DR CNRS

anne.blanc-portard arobase umontpellier.fr

BRANDT Sylvaine AI CNRS sylvaine.brandt arobase umontpellier.fr

GANNOUN Leila

MC UM2

leila.gannoun arobase umontpellier.fr

GARAI Preeti Post-Doc preeti.garai arobase umontpellier.fr

LETOURNEUR François

DR INSERM

francois.letourneur arobase umontpellier.fr

MARTIN-LAVERRAT Marianne

CR-CNRS marianne.martin arobase umontpellier.fr

MOLLE Virginie

DR CNRS

virginie.molle arobase umontpellier.fr

MOUSSOUNI Malika Doctorante malika.moussouni arobase umontpellier.fr

ROSAS OLVERA Mariana

Doctorante

mariana.rosas-olvera arob umontpellier.fr

TIFRA Annabelle Technicienne annabelle.fifra arobase umontpellier.fr
 
 

Pathogenic bacteria have developed strategies to adapt to host environment and resist to host defenses. Studies are carried out both in the context of bacterial regulation and adaptation to environment in the context of host-pathogen interactions.
Successful parasitism of macrophages by bacterial pathogens reflects the equilibrium between host and pathogen, which is established and maintained through the modulation of macrophage-signaling mechanisms. This leads to the attenuation of several cellular processes that include fusion of phagosomes with lysosomes, antigen presentation, apoptosis, and bactericidal responses initiated by the macrophages. This attenuation represents the outcome of a dynamic process wherein bacterial molecules interfere with the signaling machinery of the host cell.
Pathogens studied by our team include mycobacterial species (Mycobacterium tuberculosis and Mycobacterium marinum), Salmonella typhimurium, Pseudomonas aeruginosa, Staphylococcus aureus, Legionella pneumophila and Coxiella burnetti. These pathogens, with the exception of S. aureus and P. aeruginosa, share the ability to replicate in macrophages. Despite the lack of true intracellular replication, S. aureus and P. aeruginosa also evade the killing by macrophages and an intracellular phase may play a role in virulence. Our main goal is to decipher novel regulatory mechanisms that play a role during macrophage-pathogen interactions. Based on this knowledge, we aim to develop novel anti-virulence strategies.

 

Our research include three main axes including additional subparts:

AXIS 1. REGULATION VIA PHOSPHORYLATION OF BACTERIAL AND HOST FACTORS IMPORTANT FOR VIRULENCE (headed by V. Molle)

- Regulation of bacterial factors by Serine/Threonine Protein Kinases (STPKs) or phosphatases with a focus on factors that play a role in virulence

- Regulation of host factors by bacterial STPKs and/or phosphatases. We already have confirmed the prominent role of Ser/Thr phosphorylation in regulating essential mechanisms, but the role of these Ser/Thr kinases "outside" the bacterium remains totally unknown. The main question is: are bacterial STPKs/phosphatases able to interfere with host-adaptation mechanisms known to involve host proteins? We are confirming such secretion in cellular models and investigate host substrates.


AXIS 2. STUDY OF BACTERIAL FACTORS INVOLVED IN INTRAMACROPHAGE SURVIVAL AND IDENTIFICATION OF REGULATORY PEPTIDES DISPLAYING ANTI-VIRULENCE PROPERTIES (headed by A. Blanc-Potard)

-Role of an intramacrophage step during infection with so-called “extracellular pathogens” and study of bacterial factors specifically involved in this step. Role of an intramacrophage step during P. aeruginosa infection and study of bacterial factors specifically involved in this step. Implication of the CFTR chanel in the intramacrophage step

- Regulation of bacterial virulence factors by membrane peptides and search for “anti-virulence” peptides. Identification and functional/structural characterization of regulatory peptides displaying anti-virulence properties. Biological activity of synthetic peptides against pathogenic bacteria in infection models


AXIS 3. MECHANISMS OF MEMBRANE REMODELING DURING PHAGOCYTOSIS AND SUBVERSION BY PATHOGENIC INTRACELLULAR BACTERIA
(headed by F. Letourneur)

    - Molecular basis of membrane remodeling and protein sorting events during phagosome maturation. Characterization of key proteins essential for these processes by making use of the amoeba Dictyostelium discoideum, a phagocytic cell amenable to genetic analysis.

    - Identification of host proteins targeted by pathogenic bacteria (Mycobacterium tuberculosis, Mycobacterium marinum, and Legionella pneumophila) and subversion of host-cell defenses in D. discoideum by bacteria secreted factors.





- 2016 Publications -

S. Brelle, G. Baronian, S. Huc-Brandt, L.G. Zaki, M. Cohen-Gonsaud, M. Bischoff and V. Molle (2016) Phosphorylation-mediated regulation of the Staphylococcus aureus secreted tyrosine phosphatase PtpA. Biochemical and Biophysical Research Communications 469:619-625.

M. Catel-Ferreira, S. Marti, L. Guillon, L. Jara, G. Coadou, V. Molle, E. Bouffartigues, G. Bou, I. Shalk, T. Jouenne, X. Vila-Farrés and Dé E (2016). The outer membrane porin OmpW of Acinetobacter baumannii is involved in iron uptake and colistin binding. FEBS Letters 590:224-231.

M. Bischoff, S. Brelle, S. Minatelli and V. Molle (2016) Stk1-mediated phosphorylation stimulates the DNA-binding properties of the Staphylococcus aureus SpoVG transcriptional factor. Biochemical and Biophysical Research Communications 473:1223-1228.

A. Gueho, C. Bosmani, N. Gopaldass, V. Molle, T. Soldati and F. Letourneur (2016) Dictyostelium EHD associates with Dynamin and participates in phagosome maturation. Journal of Cell Science 129:2354-2367.

N-H Le, V. Molle, N. Eynard, M. Miras, A. Stella, F. Bardou, S. Galandrin, V. Guillet, G. André-Leroux, M. Bellinzoni, P.Alzari, L. Mourey, O. Burlet-Schiltz, M. Daffé and H. Marrakchi (2016) Ser/Thr phosphorylation regulates the Fatty Acyl-AMP Ligase activity of FadD32, an essential enzyme in mycolic acid biosynthesis. Journal of Biological Chemistry 291:22793-22805.

A. K. Sharma, D. Arora, L. K. Singh, A. Gangwal, A. Sajid, V. Molle, Y. Singh, and V. K. Nandicoori (2016) Serine/threonine protein phosphatase PstP of Mycobacterium tuberculosis is necessary for accurate cell division and survival of pathogen. Journal of Biological Chemistry 291:24215-24230.

Le Moigne C, Belon C, Goulard C, Accard G, Bernut A, Pitard B, Gaillard JL, Kremer L, Herrmann JL and Blanc-Potard AB. (2016) MgtC as a host-induced factor and vaccine candidate against Mycobacterium abscessus infection. Infect. Immun. ;84(10):2895-903.

Belon C and Blanc-Potard AB. (2016) Intramacrophage survival for extracellular bacterial pathogens: MgtC as a key adaptive factor. Front Cell Infect Microbiol. doi: 10.3389/fcimb.2016.00052

Belon C, Rosas Olvera M, Vives E, Kremer L, Gannoun-Zaki L, Blanc-Potard AB. (2016) Use of the Salmonella MgtR peptide as an antagonist of the Mycobacterium MgtC virulence factor. Future Microbiol. 11:215-25


 

- 2015 Publications -

Bernut A., Belon C., Soscia C., Bleves S., Blanc-Potard AB. Intracellular phase for an extracellular bacterial pathogen: MgtC shows the way. Microbial Cell. In press

Guzzo M., Agrebi R., Espinosa L., Baronian G.,  Molle V., Mauriello E.M., Brochier-Armanet C. and Mignot T. (2015) Evolution and Design Governing Signal Precision and Amplification in a Bacterial Chemosensory Pathway. PLoS Genetics 20;11(8):e1005460. doi: 10.1371/journal.pgen.1005460.

Belon C., Soscia C., Bernut A., Laubier A., Bleves S., Blanc-Potard AB. (2015) A Macrophage Subversion Factor Is Shared by Intracellular and Extracellular Pathogens. PLoS Pathog. 11(6):e1004969. doi: 10.1371/journal.ppat.1004969. eCollection

Besteiro S., Blanc-Potard A., Bonazzi M., Briant L., Chazal N., Cornillot E., Lentini G., Matkovic R., Sanosyan A., Tuaillon E., Van de Perre P. Montpellier Infectious Diseases - Pôle Rabelais (MID) 3rd annual meeting (2014). Infect Genet Evol. 2015 Jun;32:161-4.

Baronian G., Ginda K., Berry L., Cohen-Gonsaud M., Zakrzewska-Czerwińska J., Jakimowicz D. And Molle V. (2015) Phosphorylation of Mycobacterium tuberculosis ParB participates in regulating the ParABS chromosome segregation system. PLoS One 10:e0119907.

 

- 2014 Publications -

Baïlo N., Cosson P., Charette S.J., Paquet V.E., Doublet P., Letourneur F. (2014) Defective lysosome maturation and Legionella pneumophila replication in Dictyostelium cells mutant for the Arf GAP ACAP-A. J Cell Sci. Nov 1;127(21):4702-13. doi: 10.1242/jcs.154559. Epub 2014 Sep 4. PMID: 25189617.

Belon C., Gannoun-Zaki L., Lutfalla G., Kremer L., Blanc-Potard A. (2014) Mycobacterium marinum MgtC plays a role in phagocytosis but is dispensable for intracellular multiplication. PLoSOne.29;9(12):e116052.doi:10.1371/journal.pone.0116052. eCollection.

Gannoun-Zaki L., Belon C., Dupont C., Hilbert F., Kremer L., Blanc-Potard A. (2014).Overexpression of the Salmonella KdpF membrane peptide modulates expression of kdp genes and intramacrophage growth. FEMS Microbiol Lett. 359(1):34-41. doi: 10.1111/1574-6968.12559. Epub 2014 Sep 8.


Alibaud L., Pawelczyk J., Gannoun-Zaki L., Singh VK., Rombouts Y., Drancourt M., Dziadek J., Guérardel Y., Kremer L. (2014) Increased phagocytosis of Mycobacterium marinum mutants defective in lipooligosaccharide production: a structure-activity relationship study. J Biol Chem. 3;289(1):215-28. doi: 10.1074/jbc.M113.525550. Epub 2013 Nov 14.


Canova M.J., and Molle V. (2014) Bacterial Serine/Threonine Protein Kinases in Host-Pathogen Interactions. J Biol Chem. 289:9473-79.


Leiba J., Carrère-Kremer S., Blondiaux N., Dimala M.M., Wohlkönig A., Baulard A., Kremer L., and  Molle V. (2014) The Mycobacterium tuberculosis transcriptional repressor EthR is negatively regulated by Serine/Threonine phosphorylation. Biochem Biophys Research Commun 446:1132-1138.


Canova M.J., Baronian G., Brelle S., Cohen-Gonsaud M., Bischoff M., and Molle V. (2014) A novel mode of regulation of the Staphylococcus aureus Vancomycin-resistance-associated response regulator VraR mediated by Stk1 protein phosphorylation. Biochem Biophys Research Commun 447:165-171.


Vilchèze C., Molle V., Carrère-Kremer S., Leiba J., Mourey L., Shenai S., Baronian G., Tufariello J.,   Hartman T., Veyron-Churlet R., Trivelli X., Tiwari S., Weinrick B., Alland D., Guérardel Y., Jacobs W.R., Jr., and Kremer L. (2014) Phosphorylation of KasB Regulates Virulence and Acid-Fastness in Mycobacterium tuberculosis. Plos Pathogens 8:10(5):e1004115.


Hartmann T., Baronian G., Nippe N., Voss M., Schulthess B., Wolz C., Eisenbeis J., Schmidt-Hohagen K., Gaupp R., Sunderkötter C., Beisswenger C., Bals R., Somerville G.A., Herrmann M., Molle V., and Bischoff M. (2014) The catabolite control protein E (CcpE) affects virulence determinant production and pathogenesis of Staphylococcus aureus. J Biol Chem 289:29701-29711.


Mouammine, Lanois A., Pagès S., Lafay B., Molle V., Canova M., Girard P.A., Duvic B., Givaudan A. and Gaudriault S. (2014) Ail and PagC-related proteins in the entomopathogenic bacteria of Photorhabdus genus. PLoS One 9:e110060.


Arora G., Sajid A., Singhal A., Joshi J., Virmani R., Gupta M., Verma N., Maji A., Misra R., Baronian G., Pandey A.K., Molle V. and Singh Y. (2014) Identification of Ser/Thr kinase and forkhead associated domains in Mycobacterium ulcerans: characterization of novel association between protein kinase Q and MupFHA. PLoS Neglected Tropical Diseases 8:e3315.


Holečková N., Doubravová L., Massidda O., Molle V., Buriánková K., Benada O., Kofroňová O., Ulrych A. and Branny P. (2014) LocZ is a new cell division protein involved in proper septum placement in Streptococcus pneumoniae. MBio. 6(1):e01700-14.

 

- 2013 Publications -

G. D. Coxon., D. Craig., Corrales R.M., Vialla E., Gannoun-Zaki L., and Kremer L., (2013) Synthesis, antitubercular activity and mechanism of resistance of highly effective thiacetazone analogues. PLOS One. 8: e53162.

Saxena A.K., Roy K.K., Singh S., Vishnoi S.P., Kumar A., Kashyap V. Kr., Kremer L., Srivastava R., and Srivastava B.S. (2013) Identification and characterization of small molecule inhibitors of Rv3097c-encoded lipase (LipY) of Mycobacterium tuberculosis that selectively inhibit growth of bacilli in hypoxia. Int. J. Antimicrob. Agents. 42(1):27-35. doi: 10.1016/j.ijantimicag.2013.03.007. Epub 2013 May 14.

Sambandan D.,  D. Dao, Weinrick B.C., C. Vilchèze C., Gurcha S.S., A. Ojha A., Kremer L., Besra G.S., Hatfull G.F., and Jacobs W.R., Jr. (2013) Keto-mycolic aicds-dependent pellicle formation confers tolerance to drug sensitive Mycobacteirum tuberculosis. mBio. 7;4(3):e00222-13. doi: 10.1128/mBio.00222-13.


Leiba J., Syson K., Baronian G., Zanella-Cléon I., Kalscheuer R., Kremer L., Bornemann S., and  Molle V. (2013) Mycobacterium tuberculosis maltosyltransferase GlgE, a genetically validated anti-tuberculosis target, is negatively regulated by Ser/Thr phosphorylation. J. Biol. Chem. 288(23):16546-56. doi: 10.1074/jbc.M112.398503. Epub 2013 Apr 22.


Kumar K., Carrère-Kremer S., Kremer L., Guérardel Y., Biot C., and Kumar V. (2013)  Azide-alkyne cycloaddition en route towards 1H-1,2,3-triazole-tethered ?-lactam-ferrocene and ?-lactam-ferrocenylchalcone conjugates: synthesis and in vitro anti-tubercular evaluation. Dalton Trans. 42: 1492-1500.


Kumar K., Carrère-Kremer S., Kremer L., Guérardel Y., Biot C., and Kumar V. (2013) 1H-1,2,3-triazole-tethered isatin-ferrocene and isatin-ferrocenylchalcone conjugates: synthesis and in vitro anti-tubercular evaluation. Organometallics. In Press.


Gannoun-Zaki L., Alibaud L., and Kremer L. (2013) Point mutations within the FAS-II dehydratase components HadA or HadC contribute to isoxyl resistance in Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 57: 629-632.


Gannoun-Zaki L., Alibaud L., Carrère-Kremer S., Kremer L., and Blanc-Potard A.B.  (2013) Overexpression of the KdpF membrane peptide in M. bovis BCG results in reduced intramacrophage growth and altered cording morphology. PLOS One. 8: e60379


Corrales R.M., Leiba J., Cohen-Gonsaud M., Molle V., and Kremer L. (2013) Mycobacterium tuberculosis S-adenosyl-L-homocysteine hydrolase is negatively regulated by Ser/Thr phosphorylation. Biochem. Biophys. Res. Commun. 430: 858-864.


Hartmann T., Zhang B., Baronian G., Schulthess B., Homerova D., Grubmüller S., Kutzner E., Gaupp R., Bertram R., Powers R., Eisenreich W., Kormanec J., Herrmann M., Molle V., Somerville G.A., and Bischoff M. (2013) Catabolite control protein E (CcpE) is a LysR-type transcriptional regulator of TCA cycle activity in Staphylococcus aureus. Journal of Biological Chemistry 288:36116-36128.


Wilson R., Kumar P., Parashar V., Vilchèze C., Veyron-Churlet R., Freundlich J.S., Barnes S.W., Walker J.R., Marchiano E., Shenai S., Colangeli R., Jacobs W.R., Jr., Neiditch M.B., Kremer L., and  Alland D.  (2013) Pks13 is required for mycolic acid biosynthesis in Mycobacterium tuberculosis and is specifically inhibited by a novel class of thiophene compounds. Nat. Chem. Biol. 9(8):499-506. doi: 10.1038/nchembio.1277. Epub 2013 Jun 16.


Y. Yang A., Bhatti D., Ke,  Gonzalez-Juarrero M., Lenaerts A., Kremer L., Guérardel Y., Zhang P., and Ojha A..K. (2013) Exposure to a cutinase-like serine esterase triggers rapid lysis of multiple mycobacterial species. J. Biol. Chem. 288: 382-392.