Nontypable H. influenzae are a frequent cause of localized respiratory tract infections, including otitis media, sinusitis, bronchitis, and pneumonia. In addition, these organisms are an important cause of serious systemic infections, especially in immunocompromised hosts. The initial step in the pathogenesis of disease due to nontypable Haemophilus involves colonization of the upper respiratory tract. The investigators have demonstrated that two proteins designed HMW1 and HMW2, the prototypic members of a family of antigenically- related high-molecular-weight proteins present in most isolates of nontypable H. influenzae, mediate attachment to human epithelial cells. Based on their in vitro results, they speculate that members of this family are important colonization factors. The objective of this proposal is to characterize the molecular mechanism of the interaction between HMW1 and HMW2 and host epithelium. Initially, the process by which these proteins are presented in an active binding conformation on the surface of the organism will be defined. Subsequently, the domains of HMW1 and HMW2 involved in recognition of host cells will be identified. Finally, to confirm a role of these proteins in in vivo colonization, mutants deficient in expression of HMW1 or HMW2 or both will be examined in an animal colonization model. From a practical perspective, the results of these studies may suggest novel strategies for the prevention of nontypable H. influenzae disease. More generally, they may provide fundamental insights into the nature of the host-microbial relationship and the mechanism of protein section.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC002873-04
Application #
2713207
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Project Start
1995-06-01
Project End
1999-06-30
Budget Start
1998-06-01
Budget End
1999-06-30
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Washington University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
McCann, Jessica R; Mason, Stanley N; Auten, Richard L et al. (2016) Early-Life Intranasal Colonization with Nontypeable Haemophilus influenzae Exacerbates Juvenile Airway Disease in Mice. Infect Immun 84:2022-2030
Mell, Joshua Chang; Viadas, Cristina; Moleres, Javier et al. (2016) Transformed Recombinant Enrichment Profiling Rapidly Identifies HMW1 as an Intracellular Invasion Locus in Haemophilus influenza. PLoS Pathog 12:e1005576
Rempe, Katherine A; Porsch, Eric A; Wilson, Jolaine M et al. (2016) The HMW1 and HMW2 Adhesins Enhance the Ability of Nontypeable Haemophilus influenzae To Colonize the Upper Respiratory Tract of Rhesus Macaques. Infect Immun 84:2771-8
Rempe, Katherine A; Spruce, Lynn A; Porsch, Eric A et al. (2015) Unconventional N-Linked Glycosylation Promotes Trimeric Autotransporter Function in Kingella kingae and Aggregatibacter aphrophilus. MBio 6:
Grass, Susan; Rempe, Katherine A; St Geme 3rd, Joseph W (2015) Structural determinants of the interaction between the TpsA and TpsB proteins in the Haemophilus influenzae HMW1 two-partner secretion system. J Bacteriol 197:1769-80
McCann, Jessica R; St Geme 3rd, Joseph W (2014) The HMW1C-like glycosyltransferases--an enzyme family with a sweet tooth for simple sugars. PLoS Pathog 10:e1003977
Spahich, Nicole A; St Geme 3rd, Joseph W (2011) Structure and Function of the Haemophilus influenzae Autotransporters. Front Cell Infect Microbiol 1:5
Kawai, Fumihiro; Grass, Susan; Kim, Youngchang et al. (2011) Structural insights into the glycosyltransferase activity of the Actinobacillus pleuropneumoniae HMW1C-like protein. J Biol Chem 286:38546-57
Choi, Kyoung-Jae; Grass, Susan; Paek, Seonghee et al. (2010) The Actinobacillus pleuropneumoniae HMW1C-like glycosyltransferase mediates N-linked glycosylation of the Haemophilus influenzae HMW1 adhesin. PLoS One 5:e15888
Grass, Susan; Lichti, Cheryl F; Townsend, R Reid et al. (2010) The Haemophilus influenzae HMW1C protein is a glycosyltransferase that transfers hexose residues to asparagine sites in the HMW1 adhesin. PLoS Pathog 6:e1000919

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