Moraxella catarrhalis is a Gram-negative human mucosal pathogen, a significant cause of middle ear infections and sinusitis in infants and children and an important source of exacerbations in adults with lung disease. It is the third leading cause of otitis media (OM) and there is a high colonization rate with M. catarrhalis, as 50% of children will be colonized in the first 6 months of life. The incidence of OM is also high and as about 80% of all children under under 3 will experience at least one episode. In addition, recurrent acute OM is prevalent resulting in hearing impairment and developmental/learning problems as these children reach school age. OM is a significant source of direct and indirect health care costs and M. catarrhalis is responsible for 3 to 4 million physician office visits annually. This is considered low as diagnosis is difficult because tympanocentesis is uncommon. These facts have stimulated research aimed at identifying virulence factors involved in pathogenesis. One of the prominent surface components implicated as a virulence factor is the lipooligosaccharide (LOS). Structural analysis confirmed that M. catarrhalis LOS shares similarities with the LOS of Gram-negative human pathogens, i.e. Neisseria meningitidis, N. gonorrhoeae and Haemophilus influenzae. More importantly, these common carbohydrate epitopes are involved in virulence, i.e. adherence, biofilm formation and serum resistance. To date there has been little effort to evaluate the role of M. catarrhalis LOS in disease. The most likely reason for the lack of research in this area involves the fact that there was no data describing the genes involved in the biosynthesis and assembly of M. catarrhalis LOS and there were no defined mutants that could be used to delineate the importance of different oligosaccharide structures. We have made significant progress in this area over the previous period identifying 17 LOS genes and constructing each specific mutant. In addition, we have proposed a potential animal colonization model, together with our collaborators, which could be critical in performing in vivo studies with M. catarrhalis. We are now in a position to continue genetic and biologic studies designed to test our hypothesis that the serotype LOS structure assembled by M. catarrhalis isolates is directly related to pathogenesis. We further hypothesize that the serotype A and serotype B LOS structures may provide an advantage over the serotype C LOS structure. We will test our hypotheses by the following specific aims: (1) Determine the sequential steps involved in the assembly and biosynthesis of M. catarrhalis LOS and (2) Determine the role of M. catarrhalis LOS structures in pathogenesis. Middle ear infections are quite prevalent among you children. It is estimated that over 80% of children under the age of 5 will experience at least one of these types of infections. Moraxella catarrhalis is an organism that causes 15-20% of all bacterial middle ear infections. This generates a significant health care issue and there is significant interest in identifying vaccine targets. Therefore it is critically important to investigate bacterial components that could be vaccine antigen such as the lipooligosaccharides that are the focus of this work.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC005837-08
Application #
7712441
Study Section
Special Emphasis Panel (ZRG1-IDM-K (02))
Program Officer
Watson, Bracie
Project Start
2002-09-20
Project End
2012-11-30
Budget Start
2009-12-01
Budget End
2010-11-30
Support Year
8
Fiscal Year
2010
Total Cost
$321,985
Indirect Cost
Name
State University of New York at Buffalo
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
038633251
City
Buffalo
State
NY
Country
United States
Zip Code
14260
Luke-Marshall, Nicole R; Mang, Thomas S; Hansen, Lisa A et al. (2014) Moraxella catarrhalis is susceptible to antimicrobial photodynamic therapy with Photofrin. Lasers Surg Med 46:712-7
Luke-Marshall, Nicole R; Edwards, Katie J; Sauberan, Shauna et al. (2013) Characterization of a trifunctional glucosyltransferase essential for Moraxella catarrhalis lipooligosaccharide assembly. Glycobiology 23:1013-21
Davie, Jeremiah J; Earl, Josh; de Vries, Stefan P W et al. (2011) Comparative analysis and supragenome modeling of twelve Moraxella catarrhalis clinical isolates. BMC Genomics 12:70
Schwingel, Johanna M; Edwards, Katie J; Cox, Andrew D et al. (2009) Use of Moraxella catarrhalis lipooligosaccharide mutants to identify specific oligosaccharide epitopes recognized by human serum antibodies. Infect Immun 77:4548-58
Schwingel, Johanna M; St Michael, Frank; Cox, Andrew D et al. (2008) A unique glycosyltransferase involved in the initial assembly of Moraxella catarrhalis lipooligosaccharides. Glycobiology 18:447-55
Plamondon, Pascale; Luke, Nicole R; Campagnari, Anthony A (2007) Identification of a novel two-partner secretion locus in Moraxella catarrhalis. Infect Immun 75:2929-36
Edwards, Katie J; Schwingel, Johanna M; Datta, Anup K et al. (2005) Multiplex PCR assay that identifies the major lipooligosaccharide serotype expressed by Moraxella catarrhalis clinical isolates. J Clin Microbiol 43:6139-43
Edwards, Katie J; Allen, Simon; Gibson, Bradford W et al. (2005) Characterization of a cluster of three glycosyltransferase enzymes essential for Moraxella catarrhalis lipooligosaccharide assembly. J Bacteriol 187:2939-47
Luke, Nicole R; Allen, Simon; Gibson, Bradford W et al. (2003) Identification of a 3-deoxy-D-manno-octulosonic acid biosynthetic operon in Moraxella catarrhalis and analysis of a KdsA-deficient isogenic mutant. Infect Immun 71:6426-34