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Aims and objectives
In order to better understand how pathogens stimulate, inhibit, and manipulate host cell functions, we will analyse bacteria (K . pneumoniae, Haemophilus influenzae no tipable, S . pneumoniae, M . tuberculosis, S . aureus) and viruses (Influenza A viruses, paramyxoviruses, and respiratory syncytial virus) specified by various infection strategies . Analysis of pathways targeted by pathogens may reveal the strategies used to subvert immune responses and lead to the identification of the various Achilles heels of host defence . Although the immunomodulatory mechanisms used by viruses and bacteria may appear to be quite different, pathogens have to overcome the same host immune defences . Hence it is not surprising that there may be shared mechanisms . Consequently, the identification of a central core of systems implicated in host defence against several pathogens, which could be targeted for therapeutic manipulation, is an important goal of this project .
Our main hypothesis is that there is a common host response to infections associated with the clearance of the pathogen . In turn, pathogens try to counteract this response using conceptually similar but physically distinct processes . On the other hand, different signals (mediated by innate immune molecules and/or drugs) can tip the balance of this response, thereby affecting the outcome of the host-pathogen interaction .
The main objectives of our Programme are:
1 . To identify anti-immune strategies of different pathogens, focusing on their ability to modulate gene expression and hence cellular function via the manipulation of innate immune response.
2 . To analyse the activation of pattern recognition receptors upon infection with emphasis on these receptors launching IFN-dependent responses and controlling viral infections .
3 . To identify a set of IFN-dependent anti-infection determinants that might be common to viruses and bacteria.
4 . To evaluate the impact of molecules of the innate immune system (galectins and surfactant) on host-pathogen interactions .
5 . To uncover strategies to avoid intracellular killing . Main results until the end of 2014
• Discovery of neutralising antibodies against the pre-fusion conformation of the fusion (F) protein of the human respiratory syncytial virus (PNAS, 109, 3089-3094, 2012), which have shown great neutralising strength of this virus and represent most of the neutralising activity present in human sera .
• Pioneer analysis of the lipid A structure of the Gram-negative pathogen Klebsiella pneumoniae during an in vivo respiratory infection . It is the first study of this type that can be applied to other Gram-negative pathogens of clinical interest .
• Implementation of a new method for using bacteria microarrays as sensitive tools for exploring pathogen surface epitopes and recognition by host receptors (Campanero-Rhodes et al ., RSC Advances 2015) .
• Determination of the three-dimensional structure of ribonucleoproteins of the flu virus (Arranz et al ., Science 338 1634, 2012) .
• Identification of the attenuation and protection mechanism conferred by mutation in the Mycobacterium tuberculosis phoP gene (Solans et al., Plos Pathogen 2014), the basis for the experimental vaccination MTBVAC, currently in clinical trial phase .
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