The O'Connor Lab
Research
Molecular dissection of host-pathogen interactions
The outcome of most parasitic relationships is decided by an elaborate series of events involving hundreds of proteins. Understanding this interaction requires the analysis of the molecular mechanisms operating in both organisms and the causal relationships acting at the interface between them.
L. pneumophila is bacterial pathogen that is an environmentally-acquired through the inhalation of contaminated water aerosols. Upon entering the lung, L. pneumophila replicate within alveolar macrophages causing an often fatal form of pneumonia called Legionnaires’ disease. One avenue of research in the lab examines how L. pneumophila are able to manipulate host cell processes to survival and replicate within host cells.
Adapted from Ghosh et al., 2020
Movie by Clark, Regot & O’Connor
Many bacterial pathogens use sophisticated secretion systems to translocate bacterial proteins into the cytoplasm of their host cell. These proteins modulate a vast array of host cellular processes to promote bacterial survival and replication. Defining the molecular mechanisms by which these proteins contribute to virulence is essential in understanding how bacterial pathogens cause disease.
L. pneumophila harbors one of the largest repertoires of translocated proteins, or effectors, identified to date, deploying an arsenal of 270 proteins to modulate host cell possesses. Maintaining this large repertoire has resulted in a high degree of redundancy whereby different proteins can manipulate complementary host cell pathways providing the bacterium with multiple strategies to accomplish a single task. We use L. pneumophila pathogenesis to examine the numerous mechanisms by which an intracellular bacterial pathogen can establish infection, how it exploits host cell machinery to accomplish this and how individual proteins and their component pathways coordinately contribute to disease.
Pathogen evolution in natural reservoirs and transition to humans
In its natural environment of fresh water and soil, L. pneumophila is a parasite of a diverse array of amoebae and ciliated protozoa. Another avenue of research in the lab investigates the impact of L. pneumophila’s interaction with protozoa on its ability to cause disease.
Adapted from Park, Ghosh & O’Connor, 2020
Although the role of protozoa in the lifecycle of many bacterial pathogens is only beginning to be appreciated, it is emerging as an important aspect in the epidemiology of many water and soil-borne pathogens. Not only do protozoa function as natural reservoirs for many pathogenic microorganisms, their interaction both provides a rich environment for the evolution of novel virulence strategies and enhances invasiveness in mammalian hosts. The genetic and molecular characterization of this interaction is instrumental in understanding how bacterial pathogens persist in nature and the selective pressures that shape the evolution of virulence strategies that promote disease in humans.
The ability of L. pneumophila to grow in a diverse array of protozoan hosts and the extensive genome plasticity across the Legionella genus allows us to examine the molecular determinants of host-range and the evolution of microbial pathogenesis in nature. In fresh water and soil, L. pneumophila is destined to encounter a large number of amoebal species. This necessitates a virulence strategy that can compensate for host variation and thus, the accumulation of host-specific virulence factors. Using genetics and functional genomics, we compare and contrast the repertoires of virulence proteins required for growth in a broad assortment of hosts, how the network of molecular interactions differs between hosts and the mechanisms by which L. pneumophila copes with this variation. By examining how virulence strategies acquired for growth in amoebae can be used in mammalian hosts, we are defining how this interaction promotes the transition of bacterial pathogens from their environmental reservoirs to humans, bridging the gap between the ecology of microbial pathogens and disease.
Antibiotic Discovery - Tapping into novel sources of antibiotics
In nature, bacteria compete with one other for resources. This competition often involves releasing toxic molecules to kill their competitors. These natural products and their derivatives are a valuable source of clinically used antibiotics.
We are exploring the use of Legionella as a novel inducer of antibiotic production by a series of newly discovered strains of bacilli isolated from raw honey.
Adapted from Shin & O’Connor, 2024
