Untangling gene regulatory networks controlling host-pathogen interactions of the antimicrobial-resistant human pathogen Klebsiella pneumoniae

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The last decades have seen a rise in infections due to multi-drug-resistant bacterial pathogens, and the emergence of antibiotic resistant bacteria is one of the major challenges of our time. This serious threat to human health leads to worrying limitations of treatment options, especially against the so-called ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, K. pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter species) and we risk an "apocalyptic" post-antibiotic era if urgent action is not taken.The bacterium Klebsiella pneumoniae is an important cause of hospital- and community-acquired infections, causing for example pneumonia, skin/wound infections and catheter-associated urinary tract infections in the elderly and immunocompromised. Treatment of K. pneumoniae infections is hindered by the global spread of multidrug-resistant and hypervirulent strains, and carbapenem-resistant K. pneumoniae are classified by the WHO as a critical priority for new drug development. Of special concern are carbapenem-resistant isolates of the globally spreading strain called ST258 which frequently cause hospital-associated outbreaks and are a major contributor to the spread of carbapenem-resistance genes as they carry these on a piece of mobile DNA that can be easily spread to other bacteria. Clinical isolates of K. pneumoniae can be classified as classical or hypervirulent strains; while hypervirulent strains are a serious public health threat, the majority of Klebsiella disease burden is currently associated with classical strains. K. pneumoniae protects itself from the host immune response using many different virulence factors including a protective capsule, other surface structures and proteins that let it scavenge iron and stick to host cells. The most important of these virulence factors are currently limited to hypervirulent strains, and absent from the majority of classical K. pneumoniae isolates.Although we know a lot about the genomes of K. pneumoniae, our understanding of the mechanisms by which K. pneumoniae causes disease is still limited. This is due to limited models of infection, outside the human, and the fact that clinically important lineages are highly diverse. In order to better manage and treat K. pneumoniae infections, a deeper understanding of its ability to cause disease in humans is urgently needed. Others have recently shown how Salmonella Typhimurium (a relative of Klebsiella) is able to evade killing by antibiotics by "hiding" inside host immune cells called macrophages, but K. pneumoniae was largely believed to lack this ability. However, we have recently shown that unexpectedly a K. pneumoniae ST258 strain can actively replicate inside macrophages, and we plan to try to understand this process in order to provide the basis for better treatments of K. pneumoniae in the future.In this project, we will investigate how this strain responds to surviving inside macrophages by changing how it regulates its metabolism and growth, and how the host cell responds to the invading bacteria. We will try to reconstruct the complex control networks that regulates this ability in the bacterium, and we will compare this response to that of other related bacteria that also survive inside macrophages. Finally, we will look at other strains of K. pneumoniae from the environment, people in the community and hospital patients to see how widespread the ability is to survive inside host cells, and see if we can identify any genes or gene variants that might explain this. We believe that understanding all of these aspects will accelerate efforts to produce treatments for K. pneumoniae infection.