Acinetobacter baumannii Virulence Attributes: The Roles of Outer Membrane Protein A, Acinetobactin-mediated Iron Acquisition Functions, and Blue Light Sensing Protein A

ACINETOBACTER BAUMANNII VIRULENCE ATTRIBUTES: THE ROLES OF OUTER MEMBRANE PROTEIN A, ACINETOBACTIN-MEDIATED IRON ACQUISITION FUNCTIONS, AND BLUE LIGHT SENSING PROTEIN A by Jennifer Angeline Gaddy Acinetobacter baumannii is a gram-negative opportunistic pathogen that has emerged as a problematic organism, causing severe infections in human hosts. This is compounded by the fact that clinical isolates of this organism are often resistant to multiple types of antimicrobial therapies. To better understand the molecular mechanisms involved in pathogenicity with the long-term goal of finding targets for novel therapies of the future, the work presented in this manuscript focuses on the factors involved in the adherence to abiotic and biotic surfaces, invasion of epithelial cells, and killing of invertebrate animal models. In addition, this work presents novel data about the regulation of those factors. Adherence to biotic surfaces is often the first step of pathogenesis. It is apparent that outer membrane protein A is required for adherence of A. baumannii ATCC 19606 T cells to human respiratory epithelia. In addition, cells lacking the productionof this protein are deficient in their ability to kill eukaryotic cells such as A549 human alveolar cells and also Candida albicans tup1 filaments. Furthermore, it was proven that the death of these cells is a result of an induction of apoptosis and secreted proteins in addition to OmpA are implicated in that process. After the bacterial cell invades the A549 eukaryotic cell, it requires the function of an iron acquisition system, specifically acinetobactin biosynthesis and transport. Without these functions, bacterial cells can adhere to the surface of A549 cells, but cannot persist and replicate in the cytoplasm of the eukaryotic cell. In addition, the apoptotic induction in A549 cells is lowered when infections are performed with mutants lacking iron acquisition functions. Interestingly, A. baumannii cells lacking siderophore biosynthesis can be crossfed during infections of A549 cells via co-infection with parental strain expressing full function of siderophore biosynthesis. These results are also supported by animal model experiments using Galleria mellonella caterpillars. In addition, it was also proven that purified cell-free siderophore is capable of inducing an apoptotic response. The bacterial cell must coordinate its physiology in response to environmental stimuli to adapt to the transition from environmental reservoirs to the host niche. This work implicates blue light sensing protein A as a regulator capable of changing the proteins decorating the outer membrane in response to stimuli such as light and temperature. Two proteins which are regulated by BlsA are OmpA and the BauA siderophore receptor involved in siderophore transport. In summary, A. baumannii utilizes sensing molecules and response to mediate changes in its cellular biology in order to persist in many different environments and adapt quickly to changes in that environment. Some of these proteins are necessary for adherence, invasion, intracellular persistence and replication, as well as virulence in animal hosts. Acinetobacter baumannii Virulence Attributes: The Roles of Outer Membrane Protein A, Acinetobactin-mediated Iron Acquisition Functions, and Blue Light Sensing Protein A