Brassinga Laboratory Research Summary
Our laboratory research is focused on studying Legionella pneumophila, the causative agent of Legionnaires’ Disease. L. pneumophila and related species are facultative intracellular parasites of aquatic protozoa. L. pneumophila possesses a unique developmental cycle that alternates between vegetative replicating intracellular forms and cyst-like extracellular forms. It is proposed that cyst-like forms, either free-form or within amoebae vesicles, when aerosolized in water droplets and inadvertently inhaled by susceptible individuals, infect alveolar macrophages manifesting as an atypical pneumonia termed legionellosis or Legionnaires’ disease. Individuals at high risk of contracting the disease are very often immunocompromised such as the elderly or transplant/cancer patients, whereas healthy individuals are at low risk. Communicable transmission of L. pneumophila to other individuals has not been documented. Eradication of L. pneumophila from water is difficult as CLFs are not only resistant to chlorine and hot water, but are also protected from these factors when within protozoa. We are interested in uncovering the molecular mechanisms that control the differentiation of replicating bacteria into cyst-like forms by studying the global regulatory cascade that controls the developmental cell-cycle program.
Although equipped with an armoury of virulence factors, successful infection of alveolar macrophages by L. pneumophila is enabled by the presence of a type IV protein secretory system (T4SS) that, in analogy to a medical syringe, facilitates the delivery of effector molecules into the host cell affecting remodulation of the host cell environment. Intracellular survival of L. pneumophila within alveolar macrophages is dependent upon subversion of host cell functions including abrogation of the phagosome-lysosome fusion pathway, evasion of activated innate immune defences, successful establishment of the replicative niche and promotion of host cell survival. We are interested in how L. pneumophila is able to gain the ability to evade innate immune responses once internalized by alveolar macrophages. Recently, the free-living soil nematode Caenorhabditis elegans has been established as a host model host model for the examination of two aspects of L. pneumophila pathogenesis. In reference to the increased incidence of Legionnaires’ disease in individuals exposed to garden potting soil, the first aspect investigates the potential role of C. elegans in the ingestion, retention and dissemination of L. pneumophila in a soil environment. The passage of L. pneumophila through the C. elegans intestinal lumen highlights the plausible evolutionary origin of the ability of L. pneumophila to manipulate the innate immune response in the mammalian host cell considering the lack of an innate immune system in its natural protozoan host cell and that L. pneumophila is non-communicable among humans. The second aspect investigates the immunopathogenesis of L. pneumophila in C. elegans. In comparison, the basic framework of the innate immune systems in C. elegans and in human macrophages, are very similar if not identical in some elements. Thus, studying L. pneumophila in the C. elegans host model presents another approach in the investigation in understanding how L. pneumophila successfully infects human macrophages.
Research in our laboratory is funded by the Natural Sciences and Engineering Research Council, Canadian Foundation for Innovation, Manitoba Medical Service Foundation, Manitoba Health Research Council, and the University of Manitoba.