Moraxella catarrhalis is an important cause of otitis media in children, and lower respiratory tract infections (exacerbations) in adults with chronic obstructive pulmonary disease (COPD). The widespread use of pneumococcal conjugate vaccines in children since 2000 has caused an increased prevalence of colonization and infection by M. catarrhalis. Work on M. catarrhalis has lagged behind because the organism was previously regarded as a commensal. Given its growing importance, there is an urgent need for M. catarrhalis vaccines. Indeed, only a handful of laboratories in world study the organism. M. catarrhalis causes infection by inhabiting environmental niches contiguous with the upper respiratory tract, including the middle ear space (otitis media) and the airways in adults with COPD. The maintenance of fitness in different host milieus is of central importance in the pathogenesis of M. catarrhalis infections. We identified oligopeptide permease A (OppA), a solute binding protein of an ABC transporter system, as a promising vaccine antigen and also as a potential virulence factor. M. catarrhalis has a strict growth requirement for arginine. We showed that OppA transports arginine-containing peptides. An OppA knockout mutant is cleared more quickly from the respiratory tract than wild type in a murine model, indicating that OppA facilitates persistence of M. catarrhalis in the respiratory tract.
In Aim 1, we will investigate OppA and related transporter as virulence factors. We showed that OppA expresses epitopes on the bacterial surface, a surprising observation for a predicted soluble periplasmic protein.
In Aim 2 we will elucidate the molecular structure of OppA and related transporters in the bacterial cell wall to identify potentially protective epitopes and peptide binding regions.
Aim 3 will translate these observations to the development of vaccines to prevent M. catarrhalis infection. Vaccine candidates will be evaluated using several complementary model systems. Thus the present proposal will advance the field by: * identifying new virulence mechanisms for an understudied pathogen * elucidating structure of a vaccine antigen on which we have novel observations that challenge current thinking about cell wall structure of solute binding proteins of ABC transporter * identifying and characterizing new vaccine antigens While knowledge of the biology of otitis media and bacterial infection in COPD is advancing, it has been decades since the development of truly new prevention modalities for infection in these clinical settings. The present proposal has the potential to make fundamental advances in prevention of otitis media and exacerbations of COPD through identification and characterization of novel vaccine antigens. There is a renewed enthusiasm for vaccines for otitis media given recent promising clinical trials, creating a momentum of feasibility for this approach.
Moraxella catarrhalis causes otitis media in children and lower respiratory tract infections in adults with chronic obstructive pulmonary disease. This proposal will use state-of-the-art methods to identify and study molecules that enable the bacterium to cause these infections. Importantly, these observations will be translated into novel vaccines to prevent otitis media in children and airway infections in adults with chronic lung disease.
|Otsuka, Taketo; Kirkham, Charmaine; Brauer, Aimee et al. (2016) The Vaccine Candidate Substrate Binding Protein SBP2 Plays a Key Role in Arginine Uptake, Which Is Required for Growth of Moraxella catarrhalis. Infect Immun 84:432-8|
|Ren, Dabin; Almudevar, Anthony L; Murphy, Timothy F et al. (2015) Serum antibody response to Moraxella catarrhalis proteins OMP CD, OppA, Msp22, Hag, and PilA2 after nasopharyngeal colonization and acute otitis media in children. Vaccine 33:5809-14|
|Jones, Megan M; Murphy, Timothy F (2015) Expression of the Oligopeptide Permease Operon of Moraxella catarrhalis Is Regulated by Temperature and Nutrient Availability. Infect Immun 83:3497-505|
|Otsuka, Taketo; Kirkham, Charmaine; Johnson, Antoinette et al. (2014) Substrate binding protein SBP2 of a putative ABC transporter as a novel vaccine antigen of Moraxella catarrhalis. Infect Immun 82:3503-12|
|Jones, Megan M; Johnson, Antoinette; Koszelak-Rosenblum, Mary et al. (2014) Role of the oligopeptide permease ABC Transporter of Moraxella catarrhalis in nutrient acquisition and persistence in the respiratory tract. Infect Immun 82:4758-66|
|Murphy, Timothy F; Brauer, Aimee L; Kirkham, Charmaine et al. (2013) Role of the zinc uptake ABC transporter of Moraxella catarrhalis in persistence in the respiratory tract. Infect Immun 81:3406-13|