Deciphering microbial virulence mechanisms during Legionella pneumophila infection

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The bacterium Legionella pneumophila is the causative agent of a potentially life-threatening pneumonia called Legionnaires' disease. Upon inhalation by humans, L. pneumophila enters the human lung where it can infect and replicate within alveolar macrophages, specialized immune cells. Instead of being degraded by macrophages, L. pneumophila uses the infected cell for its intracellular replication cycle. If not treated promptly, this respiratory infection ends fatal in up to 30 percent of all cases. The number of Legionnaires' disease cases in the U.S. has increased four-fold over the past 15 years, making L. pneumophila a significant health threat and a considerable economic burden. We are committed to studying how Legionella can escape our immune system so that we can develop better ways to prevent this from happening. Legionella is ubiquitously found in freshwater habitats such as cooling towers, faucets and shower heads, or water fountains. Major outbreaks of Legionnaires' disease occur when water from contaminated sources is aerosolized and subsequently inhaled by humans. Immune-compromised individuals, infants, or the elderly are at an elevated risk of contracting an infection. Like many other microbial pathogens, L. pneumophila have developed a variety of strategies to infect their human host and to cause disease. They use a specialized protein complex called Type IV Secretion System to inject an abundance of proteins, or effectors, into the infected host cell. The effectors modulate signaling events within the host in order to create conditions favorable for L. pneumophila. Obtaining a detailed understanding of Legionella's effectors and itsvirulence strategies is essential for the development of novel therapeutics capable of preventing and treating this dangerous pneumonia and will profoundly improve people's lives and wellbeing. Over the past funding period, we have made significant progress in deciphering some of the virulence strategies of L. pneumophila. One intriguing finding was that L. pneumophila exploits the human Hippo signaling pathway. The Hippo pathway is highly conserved in all eukaryotic life forms where it is best known for its role in controlling cell development and differentiation. Yet, our finding now suggests that this pathway also plays an important role during microbial infection. Specifically, we discovered that L. pneumophila encodes an effector called LegK7 that mimics the human Hippo kinase, thereby taking control of the Hippo signaling route with the goal of causing changes in host cell physiology that promotes intracellular bacterial growth. Pharmacological interference with this molecular mimicry rendered human cells less susceptible to L. pneumophila growth, providing us with a new way to treat infections by this pathogen. Another notable finding was the existence of a previously undescribed membrane targeting domain in one of the Legionella effectors. This protein, called SidD, localizes to a specific membranes within infected cells in order to properly execute its function. Not only did we reveal at a mechanistic and structural level how this domain can accomplish membrane targeting of SidD, but we also developed strategies to interfere with the targeting process and thus with the function of the Legionella effector. In a third project, we have taken the first step towards the development of smarter antibiotics that selectively target pathogens. Multi-drug-resistant pathogens are an emerging threat to human health. Since conventional antibiotics target not only the pathogen but also eradicate the beneficial human microbiota, they often cause additional clinical complications. Thus, there is an urgent need for the development of therapeutics that selectively target pathogens without affecting beneficial commensals. The bacterial type IV secretion system (T4SS) is essential for the virulence of a variety of pathogens but dispensable for bacterial viability in general and can, thus, be considered a pathogens Achilles heel. By identifying small molecules that interfere with the function of the T4SS from Legionella pneumophila and another important human pathogen, Coxiella burnetii, our study represents the first step in our pursuit towards precision medicine by developing pathogen-selective therapeutics capable of treating the infections without causing harm to commensal bacteria.