Host-bacteria interactions and anti-infectious strategies (V. Molle)

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In our team we decided to study how pathogenic bacteria interact with their hosts in order to identify anti-infectious strategies. To do so:

  • we study the adaptation of extracellular pathogens (Staphylococcus aureus, Pseudomonas aeruginosa) in host cells during the infectious processes
  • we investigate the role of bacterial virulence factors secreted during infection by different pathogens such as tuberculosis, L. pneumophila, S. aureus.
  • we develop zebrafish pathological models to study specific infections such as diabetic foot infection or cystic fibrosis.

 

Research projects

Theme 1: Host-pathogen interactions mediated by bacterial kinases and phosphatases

Theme leader : Dr. Virginie MOLLE

Our research activities focus on the study of pathogenic bacteria in order to elucidate the molecular scale of the mechanisms responsible for their virulence and, from there, to draw lessons in terms of therapy and prevention. This approach also involves, and perhaps above all, to characterize the signals that trigger this infection.
In bacteria, signal transmission and gene regulation is regulated, in the majority of cases, by the classic so-called "two-component" systems, involving a membrane protein "sensor" (a histidine kinase, allowing recognition of the stimulus exterior) and its associated intracellular regulator.
Interestingly, in pathogenic bacteria such as Mycobacterium tuberculosis (Mtb), or Staphylococcus aureus, we observe, in addition to this classic system, the presence of Serine / Threonine / Tyrosine Protein Kinases (STTPKs) and phosphatases similar to eukaryotic kinases.
Our research contribute to demonstrate the direct relationship between the phosphorylation of proteins and the virulence of these bacteria.
The aim of our research is to lead to a better understanding of the regulatory mechanisms via phosphorylation, which represents a central process allowing pathogenic bacteria to adapt and survive in the infected host.
In addition, a better understanding of these regulatory mechanisms opens the way to new therapeutic developments.

THEME 2: BACTERIAL FACTORS INVOLVED IN INTRAMACROPHAGE SURVIVAL AND ANTIVIRULENCE STRATEGIES

Theme leader : Dr. Anne BLANC-POTARD

We aim to provide a better understanding of an intramacrophage phase for extracellular pathogens, especially in the cystic fibrosis context, as well as identify novel antimicrobial molecules targeting factors involved in intramacrophage survival.

Intracellular bacterial pathogens, as Mycobacterium tuberculosis or Salmonella enterica, can replicate within phagocytic cells. In contrast, extracellular pathogens, as Staphylococcus aureus or Pseudomonas aeruginosa, avoid phagocytosis, thus promoting extracellular multiplication. However, a phase of intracellular residence can be of importance for so-called extracellular pathogens. Focusing mainly on P. aeruginosa, our objective is to investigate the function and expression of specific bacterial virulence factors (MgtC, OprF, T3SS, ExoS ..) involved in an intramacrophage stage. We then aim to decipher the role if this intracellular phase in the establishment, dissemination and persistence of the infection, using zebrafish embryos, which offers powerful tools to study host-pathogens interactions. Embryos deficient for CFTR channel are used as surrogate for cystic fibrosis context.

Morevover, uprising antibiotic resistance in various bacteria urges for the development of novel antibacterial strategies. Our studies of factors involved in intramacrophage survival have provided new targets for antivirulence strategies. We have recently identified hydrophobic peptides that reduce bacterial intramacrophage survival upon overexpression or exogenous addition. Our current goal is to decipher the mechanisms of action of synthetic peptides of interest and to test their antivirulence activity against various bacteria and in the zebrafish infection model. Through collaborations, we also test the efficiency of molecules inhibiting other specific targets (as NADK, T3SS ..) against P. aeruginosa using macrophage infection model and zebrafish infection model.

Theme 3: role of post-translational modifications in intracellular bacterial survival

Theme leader : Dr. Laila GANNOUN



Our projects investigate the involvement of post-translational modifications (PTM) in bacterial pathogenesis and host–pathogen interactions. As PTMs play fundamental roles in cellular physiology, it is not surprising that pathogens interfere in many different ways with the PTMs of their host to promote their own survival and replication. We aim to decipher the mechanisms developed by the pathogenic bacteria, S. aureus, to survive inside host cells. We focus on host adaptation during macrophage infection with S. aureus based on post-translational modifications.

First, we study secreted bacterial signalling proteins such as the low molecular weight protein tyrosine phosphatases (LMW-Ptps) PtpA and PtpB, in order to understand their role(s) during infection and/or adaptation of S. aureus to host environmental stress, leading to yet unexplored S. aureus modes of host-pathogen interactions such as the modulation of phosphorylation status of host signalling networks

Moreover, we explore  the  role  of SUMOylation, a novel PTM involved in bacterial intracellular survival. This PTM can modify host proteins and/or bacterial secreted proteins after host cell infection. Our goal is to (i) decipher SUMOylation regulation of secreted virulence factors and/or host proteins involved in S. aureus intracellular survival and virulence, (ii) identify and characterize SUMO-modified proteome (or SUMOylome) during infection, and (ii) target SUMOylation of host proteins or secreted during infection to develop anti-virulence strategies.

Theme 4: BACTERIAL PATHOGEN MANIPULATION OF HOST MEMBRANE TRAFFICKING

Theme leader : Dr. François LETOURNEUR



Our projects are aimed at understanding how pathogenic bacteria can manipulate host functions to evade host defenses and replicate intracellularly. This question belongs to our long-standing analysis of membrane trafficking events taking place during phagocytosis and phagosome maturation in the professional phagocyte Dictyostelium discoideum. This amoeba is an advantageous model organism to analyse the virulence of several pathogenic bacteria.

Phagocytosis of two pathogenic bacteria are being studied: Legionella pneumophila and Mycobacterium marinum. These pathogens replicate in D. discoideum using distinct mechanisms based on the injection of effector proteins into host cells to alter normal cellular processes. Our goal is to identify novel bacterial effectors and cognate host targets to decipher their precise role in virulence. The knowledge acquired through D. discoideum will be next extended to mammalian cells.

 

Team members
Publications
Collaborations
Grants

Head of the team


Virginie MOLLE

Virginie MOLLE
Research Director (DR) CNRS
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LPHI  Laboratory of Pathogen Host Interactions
UMR 5235 - Université Montpellier
Place Eugène Bataillon, Bât. 24, CC107, 2ème étage
34095 Montpellier cedex 5

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