We investigate new molecular facets of host-pathogen interactions using Listeria monocytogenes as model organism of intracellular parasitism to design new therapeutic strategies against gram positive pathogens. Using in vitro / in vivo models, we aim to decipher how bacterial pathogens organize their surface and control gene expression to promote virulence, and develop new antimicrobial approaches.
Listeria monocytogenes (Lm) is a human bacterial food-borne pathogen being the most frequent cause of death due to the consumption of contaminated food in Europe. We have been studying the Lm infectious process for more than 15 years and greatly contributed to its understanding, identifying and characterizing many bacterial and host factors involved in Lm infection.
In particular, we unraveled new mechanisms used by Lm to modify its surface and adapt its genome expression to promote infection. We performed the first transcriptome of bacteria growing inside mouse organs, revealing how Lm adapts its genome expression for virulence and identifying novel virulence factors. We showed how Lm glycosylates its wall teichoic acids to promote resistance to antimicrobial peptides, and the anchoring of surface virulence factors. We revealed that the Lm metal efflux pump repressor CadC is highly expressed during late infection stages, modulating lipoprotein processing and host immune response to promote infection. We also identified a novel Lm virulence regulator (MouR), solved its three-dimensional structure and showed that, by directly binding to the promoter of the Agr quorum sensing system, MouR modulates chitinase activity, biofilm formation and virulence.
Our work reveals how pathogens modify their surface to resist to host defenses, and control gene expression to promote virulence. These new mechanisms are now being explored as potential targets for the design of new therapeutic approaches against gram positive bacteria.
P. Cossart, Institut Pasteur-Paris
S. Raposo Filipe, ITQB-Oeiras
F. Garcia-del Portillo, CSIC-Madrid
M. Loessner, ETH-Zurich
J. Cabral, i3S-Porto
NORTE-01-0145-FEDER-030020 - Cell Wall glycosylation: an original target for innovative antimicrobial strategies against Gram-positive pathogens.
NORTE-01-0145-FEDER-000012 – Structured Program on Bioengineered Therapies for Infectious Diseases and Tissue Regeneration.
MouR controls the expression of the Listeria monocytogenes Agr system and mediates virulence. Nucleic Acids Research46(18):9338-9352, 2018. [Journal: Article] [CI: 10] [IF: 11,1]
DOI: 10.1093/nar/gky624 SCOPUS: 85054896319. .
Carvalho F., Sousa S., Cabanes D.,
l-Rhamnosylation of wall teichoic acids promotes efficient surface association of Listeria monocytogenes virulence factors InlB and Ami through interaction with GW domains. Environmental Microbiology20(11):3941-3951, 2018. [Journal: Article] [CI: 8] [IF: 5,1]
DOI: 10.1111/1462-2920.14351 SCOPUS: 85056596957. .
Pombinho R., Camejo A., Vieira A., Reis O., Carvalho F., Almeida M.T., Pinheiro J.C., Sousa S., Cabanes D.,
Listeria monocytogenes CadC regulates cadmium efflux and fine-tunes lipoprotein localization to escape the host immune response and promote infection. Journal of Infectious Diseases215(9):1468-1479, 2017. [Journal: Article] [CI: 9] [IF: 5,2]
DOI: 10.1093/infdis/jix118 SCOPUS: 85021919420. .
Pinheiro J., Reis O., Vieira A., Moura I.M., Moreno L.Z., Carvalho F., Pucciarelli M.G., García-del Portillo F., Sousa S., Cabanes D.,
Listeria monocytogenes encodes a functional ESX-1 secretion system whose expression is detrimental to in vivo infection. Virulence8(6):993-1004, 2017. [Journal: Article] [CI: 8] [IF: 3,9]
DOI: 10.1080/21505594.2016.1244589 SCOPUS: 84992702646. .
Mesquita F.S., Brito C., Mazon Moya M.J., Pinheiro J.C., Mostowy S., Cabanes D., Sousa S.,
Endoplasmic reticulum chaperone Gp96 controls actomyosin dynamics and protects against pore-forming toxins. EMBO Reports18(2):303-318, 2017. [Journal: Article] [CI: 9] [IF: 8,7]
DOI: 10.15252/embr.201642833 SCOPUS: 85007487818. .
Carvalho F., Atilano M.L., Pombinho R., Covas G., Gallo R.L., Filipe S.R., Sousa S., Cabanes D.,
L-Rhamnosylation of Listeria monocytogenes Wall Teichoic Acids Promotes Resistance to Antimicrobial Peptides by Delaying Interaction with the Membrane. PLoS Pathogens11(5):, 2015. [Journal: Article] [CI: 38] [IF: 7]
DOI: 10.1371/journal.ppat.1004919 SCOPUS: 84930354332. .
Leitão E., Costa A.C., Brito C., Costa L., Pombinho R., Cabanes D., Sousa S.,
Listeria monocytogenes induces host DNA damage and delays the host cell cycle to promote infection. Cell Cycle13(6):928-940, 2014. [Journal: Article] [CI: 21] [IF: 4,6]
DOI: 10.4161/cc.27780 SCOPUS: 84897994129. .
Carvalho F., Sousa S., Cabanes D.,
How Listeria monocytogenes organizes its surface for virulence. Frontiers in Cellular and Infection Microbiology4(APR):, 2014. [Journal: Review] [CI: 33] [IF: 3,7]
DOI: 10.3389/fcimb.2014.00048 SCOPUS: 84924841119. .
Lebreton A., Lakisic G., Job V., Fritsch L., Tham T.N., Camejo A., Matteï P.J., Regnault B., Nahori M.A., Cabanes D., Gautreau A., Ait-Si-Ali S., Dessen A., Cossart P., Bierne H.,
A bacterial protein targets the BAHD1 chromatin complex to stimulate type III interferon response. Science331(6022):1319-1321, 2011. [Journal: Article] [CI: 114] [IF: 31,2]
DOI: 10.1126/science.1200120 SCOPUS: 79952515250. .
Camejo A., Buchrieser C., Couvé E., Carvalho F., Reis O., Ferreira P., Sousa S., Cossart P., Cabanes D.,
In vivo transcriptional profiling of Listeria monocytogenes and mutagenesis identify new virulence factors involved in infection. PLoS Pathogens5(5):, 2009. [Journal: Article] [CI: 145] [IF: 9]
DOI: 10.1371/journal.ppat.1000449 SCOPUS: 67249147690. .