title: ATP-Binding Cassette (ABC) Transporters of the Human Respiratory Tract Pathogen, Moraxella catarrhalis: Role in Virulence.
abstract: Moraxella catarrhalis is a human respiratory tract pathogen that causes otitis media (middle ear infections) in children and respiratory tract infections in adults with chronic obstructive pulmonary disease. In view of the huge global burden of disease caused by M. catarrhalis, the development of vaccines to prevent these infections and better approaches to treatment have become priorities. In previous work, we used a genome mining approach that identified three substrate binding proteins (SBPs) of ATP-binding cassette (ABC) transporters as promising candidate vaccine antigens. In the present study, we performed a comprehensive assessment of 19 SBPs of 15 ABC transporter systems in the M. catarrhalis genome by engineering knockout mutants and studying their role in assays that assess mechanisms of infection. The capacity of M. catarrhalis to survive and grow in the nutrient-limited and hostile environment of the human respiratory tract, including intracellular growth, account in part for its virulence. The results show that ABC transporters that mediate uptake of peptides, amino acids, cations and anions play important roles in pathogenesis by enabling M. catarrhalis to 1) grow in nutrient-limited conditions, 2) invade and survive in human respiratory epithelial cells and 3) persist in the lungs in a murine pulmonary clearance model. The knockout mutants of SBPs and ABC transporters showed different patterns of activity in the assay systems, supporting the conclusion that different SBPs and ABC transporters function at different stages in the pathogenesis of infection. These results indicate that ABC transporters are nutritional virulence factors, functioning to enable the survival of M catarrhalis in the diverse microenvironments of the respiratory tract. Based on the role of ABC transporters as virulence factors of M. catarrhalis, these molecules represent potential drug targets to eradicate the organism from the human respiratory tract.
authors.affiliation: Clinical and Translational Research Center, University at Buffalo, the State University of New York, Buffalo, NY, United States of America.|Division of Infectious Diseases, Department of Medicine, University at Buffalo, the State University of New York, Buffalo, NY, United States of America.|Department of Microbiology, University at Buffalo, the State University of New York, Buffalo, NY, United States of America.
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Murphy
authors.affiliation: Clinical and Translational Research Center, University at Buffalo, the State University of New York, Buffalo, NY, United States of America.|Division of Infectious Diseases, Department of Medicine, University at Buffalo, the State University of New York, Buffalo, NY, United States of America.
authors.forename: Aimee L
authors.initials: AL
authors.lastname: Brauer
authors.affiliation: Clinical and Translational Research Center, University at Buffalo, the State University of New York, Buffalo, NY, United States of America.|Division of Infectious Diseases, Department of Medicine, University at Buffalo, the State University of New York, Buffalo, NY, United States of America.
authors.forename: Antoinette
authors.initials: A
authors.lastname: Johnson
authors.affiliation: Clinical and Translational Research Center, University at Buffalo, the State University of New York, Buffalo, NY, United States of America.|Division of Infectious Diseases, Department of Medicine, University at Buffalo, the State University of New York, Buffalo, NY, United States of America.
authors.forename: Charmaine
authors.initials: C
authors.lastname: Kirkham
mesh_terms: D000072283:A549 Cells; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism / Q000382:microbiology; D016680:Genome, Bacterial / Q000235:genetics; D006801:Humans; D008807:Mice, Inbred BALB C; D001936:Moraxella catarrhalis / Q000378:metabolism* / Q000472:pathogenicity*; D012137:Respiratory System / Q000378:metabolism / Q000382:microbiology; D012141:Respiratory Tract Infections / Q000235:genetics / Q000378:metabolism*; D014774:Virulence
chemical_list: D018528:ATP-Binding Cassette Transporters; D001426:Bacterial Proteins