Deciphering Klebsiella pneumoniae strategies to subvert host defences

The growing number of organisms resistant to currently available antibiotics has become a major public health threat worldwide. In the long-term we might not be able to treat infectious diseases due to the lack of effective therapeutic agents. Therefore there is a need to develop effective therapeutics based on new targets and approaches. One of the most promising approaches is to develop innovative therapies based on the modulation of the host-microorganism interface, specifically to target the strategies employed by the microorganisms to manipulate for their own benefit host defense responses.

Klebsiella pneumoniae is a microorganism causing a wide range of infections, from urinary tract infections to pneumonia. The latter is particularly devastating among immunocompromised patients. K. pneumoniae is a member of the so-called ESKAPE group of microorganisms to emphasize that they effectively "escape" the effects of antibacterial drugs. Therefore it is both urgent and necessary to better understand Klebsiella infection biology to be able to design new strategies to treat K. pneumoniae infections.

Previous studies from the laboratory support the notion that Klebsiella targets key cellular pathways to prevent the activation of host defense responses. Analysis of pathways targeted by Klebsiella should reveal the strategies used to subvert immune responses and lead to the identification of the various Achilles heels of host defence. By applying a multidisciplinary approach, the overall purpose of this proposal is to expand our current understanding of the strategies used by Klebsiella to survive in the lung. We will dissect how Klebsiella antagonizes the activation of the main pathways controlling the majority of host defense responses upon infection. We will study at the molecular level how Klebsiella perturbs the activation of the receptors that the host employs to sense the presence of an infection. And, finally, we will decipher how Klebsiella manipulates the modifications that the cells used to rapidly, locally and specifically modify activity or interactions of key proteins implicated in sensing/responding infections.

The anticipated results of this proposal should initiate the process of the development of drugs which can serve as therapeutic agent to treat Klesiella infections effectively and perhaps other infections as well. It might be possible that there are drugs already approved for use in humans but used for purposes unrelated to antimicrobial activity, that modulate the target identified in the context of host-Klebsiella interactions. This will significantly short cut or even bypass the drug-development process. It is therefore believed that such targets - if found and validated during the research - will meet big interest at pharmaceutical companies, involved in the development of anti-infective agents.

During infection, microbial presence is continuously monitored by receptors recognizing evolutionary conserved structures. Pathogen recognition is associated with the activation of few regulators and signaling pathways that control the expression of host defence systems, chiefly the inflammatory response. Subversion of this fast-acting response is considered important for pathogen survival during the early stages of infection.
This proposal aims to gain a holistic understanding of the strategies used by Klebsiella pneumoniae to counteract the activation of host defense pathways. There is scant evidence on K. pneumoniae pathogenesis at the molecular and cellular level. Therefore it is both urgent and necessary to better understand its pathophysiology to be able to design new strategies to treat Klebsiella infections. My laboratory has demonstrated that Klebsiella subverts the activation of host defence processes (receptor-mediated Klebsiella recognition, NF-kB activation) to survive in the lung. This proposal will pursue ambitious questions at the forefront of research in infection biology: (i) to decipher how Klebsiella manipulates NF-kB and IFN-dependent pathways; (ii) to determine whether Klebsiella perturbs the subcellular location of pattern recognition receptors to manipulate their function; (iii) to establish how Klebsiella takes control over host post-transcriptional modifications to alter cellular responses.
By applying a multidisciplinary approach encompassing microbiology, cell biology, functional genomics, and immunology, this proposal will expand our current understanding of the strategies used by Klebsiella to survive in the lung. On top of this, this proposal will shed new light and open new avenues of research into the complexity of host-pathogen interactions. A better understanding of the host-pathogen interactions offers the potential for pharmacological intervention by targeting the host side.

Who will benefit from this research? Academics will be the main short to medium term beneficiary, as the research will provide knowledge to understand how pathogens counteract the activation of host defences. This is one of the most competitive areas of research in the field of microbial pathogenesis. The main collaborative interactions will be with Prof Philippe Sansonetti (Institut Pasteur) on Klebsiella infection biology; Prof Thomas Meyer (Max Planck Institute Infection Biology) following up the high-throughput screening performed (Frank et al 2013 Cellular Microbiology, in press); and with the partners of the Marie Curie ITN INBIONET working on viruses, IFN signaling pathways, and immune regulation (Prof Andrew Bowie [Trinity College Dublin], Prof Richard Randall [University St. Andrews], and Prof Pavel Kovarik [University of Vienna]). The research will enhance the career development of Dr. Frank (named Research Co-Investigator) and the requested PDRA. Dr. Frank was responsible for a significant amount of the background research. The requested PDRA will receive training in some of the most novel aspects of host-pathogen interactions with emphasis on innate immune signaling. Industry: The growing number of organisms resistant to available antibiotics has become a public health threat worldwide, being Klebsiella a paradigm of an emerging pathogen. There is a need to develop effective therapeutics based on new targets and approaches. The work described in this proposal is fundamental research into the molecular mechanisms that are beginning to emerge by which pathogens manipulate host defense responses. As such it is not reasonable to expect an immediate impact in terms of a new drug to combat infections. Nevertheless, one of the most promising approaches is to develop therapies based on targeting the strategies employed by pathogens to manipulate for their own benefit early innate immune responses. Then it is expected that the anticipated results will lead to the development of innovative therapies based on the modulation of the host-Klebsiella interface. General public: Infections are one of the major global threats that are unfortunately very likely to become more urgent in the near future. It is not appropriate to generate an atmosphere of fear since medical care in UK is at a very high level. However, it is advisable to increase public awareness about the potential threats and to provide the UK national regulatory bodies, with a top-class knowledge platform to maintain the unique position of UK as an area of research excellence on infection biology.
How will they benefit from this research?: Knowledge of value to the academic sector will be communicated by publication in peer-reviewed journals, oral and poster presentations at conferences and via invited lectures. Exchange of staff and students will promote knowledge transfer between collaborative groups. Staff working on the project will receive training on complementary skills (group management, know-how transfer, and entrepreneurship) which together with the cutting-edge research training received will give them all options for either an excellent career in academia, industry, or to develop a business plan for their own start-up enterprise. Knowledge transfer to industry on new targets to treat infections might have economic potential since royalty payments can reach numbers in the magnitude of several millions or tens of millions. This new treatment(s) will benefit the UK health system. The grant will have impact on the wider public sector by continuing our program of scientific communication. The laboratory hosts undergraduates to engage them in the fundamentals of scientific research. An E-Newsletter, blog posts (Blog Cést les microbes), and video clips on infection biology will serve to disseminate our research work. Social media will be targeted via Twitter (@josebengoechea). Both PDRAs will be involved in the public communication activities of this project.