Our laboratory studies two important bacterial pathogens, Legionella pneumophila and Stenotrophomonas maltophilia. We employ a multi-faceted approach toward understanding the pathogenesis and natural history of bacterial infectious disease, with the hope that basic insights will lead to new methods of disease prevention, diagnosis, or treatment.
Legionella pneumophila
L. pneumophila, the agent of Legionnaires’ disease, is a classic environmental, opportunistic pathogen. Strains of this gram-negative bacterium are widespread within aquatic environments throughout the world. Due to its broad distribution within natural waters, L. pneumophila also exists within many man-made aquatic environments; recent surveys indicate that it is present in 60% of large buildings, including hospitals and hotels. The legionellae can infect humans following the inhalation of contaminated aerosols generated by air-conditioners, fountains, showers, humidifiers, whirlpools, and other devices. The ubiquity of L. pneumophila and the widespread use of aerosol-generating devices ensure that many individuals are exposed to the Legionnaires’ disease bacterium. In the lower respiratory tract, L. pneumophila invades and proliferates to high numbers within alveolar macrophages and can, if unchecked, result in fatal pneumonia. The more serious forms of legionellosis are restricted to immunocompromised individuals, including transplant patients, the elderly, and smokers. The Legionella organism is a significant cause of both community-acquired and hospital-acquired pneumonia, accounting for an estimated 1-30 percent of cases with more than 25,000 cases of Legionnaires’ disease per year in the US. Increases in the numbers of immunocompromised and elderly individuals signal that opportunistic pathogens, such as L. pneumophila, will continue as health problems. The advent of legionellosis as a clinical entity clearly illustrates how changes in our environment (in this case, the widespread use of aerosol generators) can expose us to potentially harmful microbes.
The aim of our research is to characterize the bacterial genes and gene products that promote the occurrence of Legionnaires’ disease. In a broad sense, legionellosis is the consequence of a bacterium’s capacity to flourish within both man-made water systems and the human lung. On the one hand, the aquatic distribution of L. pneumophila is a result of the bacterium’s ability to replicate extracellularly in multi-organismal biofilms as well as intracellularly within amoebae. On the other hand, the intrapulmonary spread of the legionellae is facilitated by the infection of alveolar macrophages and epithelia, the elaboration of toxins and degradative enzymes, and evasion of innate immunity functions of the host. It is widely believed that the ability of L. pneumophila to parasitize macrophages is derived from its “prior” adaptation to intracellular growth within aquatic protozoans. This evolutionary paradigm has now proven to have relevance for a wide variety of bacterial pathogens.
Much of the pathogenesis of L. pneumophila is mediated by secreted factors that damage host tissue, subvert host defenses, or promote nutrient assimilation. We have discovered a Legionella secretion apparatus (type II secretion) that is absolutely critical for virulence and the intracellular infection process in both amoebae and mammalian cells. Current efforts are aimed at defining the > 25 type II-secreted proteins and their precise functions in the lung and within host cells. Some of these proteins appear to be entirely novel, having no homologs outside of the Legionella genus. Another secreted factor that we study is a surfactant that mediates a form of bacterial motility known as sliding. This secreted molecule, which we believe is a lipoprotein or lipopeptide, also confers antimicrobial activity against other types of legionellae. A third class of secreted molecules that we study is that which mediates iron acquisition. Among these factors are a ferric iron chelating molecule (siderophore) known as legiobactin and a ferric iron-reducing pigment known as HGA-melanin. The export and import of legiobactin is proving to be unique among bacterial iron assimilation systems.
Stenotrophomonas maltophilia
S. maltophilia is an environmental gram-negative bacterium that is being increasingly associated with an array of human infections, including most notably pneumonia. The emergence of S. maltophilia as a significant health concern is due in part to its marked antibiotic resistance. Despite its growing importance in the clinical arena, very little is known about the pathogenesis of S. maltophilia. Thus, our lab has developed murine models of lung infection, genetic tools for manipulation, and is currently trying toidentifying virulence factors produced by this important new pathogen. This includes the Type 2 Secretion System (T2SS), Type 4 Secretion System (T4SS), and siderophores.