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.
Highlights
Moraxella catarrhalis is an exclusively human pathogen that is a common cause of otitis media in children and respiratory tract infections in adults with chronic obstructive pulmonary disease [1,2,3,4]
A genome mining approach to identify putative vaccine antigens led to the identification of three substrate binding proteins (SBPs) of ATPbinding cassette (ABC) transporters as promising vaccine antigens for M. catarrhalis: oligopeptide permease A (OppA) substrate binding protein 2 (SBP2) and CysP. [6,7,8]
To begin to understand the potential role of these SBPs in infection caused by M. catarrhalis, we generated knockout mutants of each and assessed the mutants in parallel with the wild type strain in growth characteristics, the capacity to adhere to and invade human respiratory epithelial cells and their capacity to persist in the lungs in a mouse pulmonary clearance model
Summary
Moraxella catarrhalis is an exclusively human pathogen that is a common cause of otitis media (middle ear infections) in children and respiratory tract infections in adults with chronic obstructive pulmonary disease [1,2,3,4]. To identify vaccine antigens for M. catarrhalis, we used a genome mining approach to predict genes that encode proteins that are expressed on the bacterial surface and assessed selected proteins as putative vaccine antigens [5]. This approach led to the discovery of three substrate binding proteins (SBPs) of ATPbinding cassette (ABC) transporters that are promising vaccine antigens that are in various stages of development [6,7,8]. In eukaryotes, they consist of two transmembrane permease domains and two ATPase domains and function primarily in mediating efflux of molecules. The SBPs bind a wide range of molecules, including ions, amino acids, peptides, lipoproteins and carbohydrates, and are key determinants of substrate specificity of ABC transport systems
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