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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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Bacterial Vaccine Safety: Identify Genetic Determinants of Disease in Moraxella Catarrhalis

Principal Investigator: Wei Wang, PhD
Office / Division / Lab: OVRR / DBPAP / LBP


General Overview

Moraxella (Branhamella) catarrhalis, an unencapsulated gram-negative bacterium, once thought only as one of harmless inhabitants on the mucosal surface of the human upper respiratory tract. This bacterium has recently been recognized as one of the causes of bacterial infectious diseases in human upper and lower respiratory tracts. The burden of M. catarrhalis infectious disease upon United States healthcare system is substantial with regard to both patient morbidity and health care expenditures.

In infants and very young children, M. catarrhalis is one of three most common causes of acute otitis media (also known as middle ear infection), the other two pathogens are Streptococcus pneumonia and Haemophilus influenza. Following each incidence of acute otitis media, fluid persists in the middle ear for a period of time up to months. Studies indicate that children who suffer prolonged middle ear effusions during the first three years of life score lower on tests of speech, language, and cognitive abilities than do their disease-free peers. Otitis media is the most common reason for doctor visits by very young children and is responsible for almost half of the antimicrobial prescriptions written for children under ten years old of age. It is reported that the successful serotype-specific vaccines against S. pneumonia and H. influenza type b (Hib) have reduced the overall incident of otitis media; however, otitis media caused by non-vaccine respiratory pathogens, such as non-typeable H. influenzae (NTHi) and M. catarrhalis has risen. Therefore, the development of vaccine against M. catarrhalis infection is crucial for a better overall control of otitis media.

In adults with chronic obstructive pulmonary disease (COPD), M. catarrhalis is an important cause of infectious exacerbations of COPD. It was recently estimated that as many as 2 million to 4 million exacerbations of COPD in the United States can be attributed to M. catarrhalis each year. Infectious exacerbations of COPD significantly deteriorate patients' quality of life and result in a notable amount of morbidity and mortality. The total estimated cost for COPD in 2007 was 46.7 billion dollars, and COPD is projected to become the third leading cause of death worldwide by 2020.

The mechanism underlying the ability of M. catarrhalis to causes disease has not been studied. It is a known fact that nasopharyngeal colonization with M. catarrhalis is common throughout infancy and a high rate of colonization with this organism is associated with an increased risk of otitis media. Therefore, the ability of M. catarrhalis to colonize human mucosal surface of the nasopharynx is thought to be crucial for causing disease because this event provides a foothold for M. catarrhalis in its human host. Most of research efforts on M. catarrhalis studies have been focused on identifying surface proteins that facilitate the attachment of this pathogen to human cells in vitro. However, candidates of vaccine potentials for protecting against M. catarrhalis infection remain to be identified.


Scientific Overview

The studies of biomarkers for development of vaccine against M. catarrhalis infections have identified several outer-membrane proteins functioning as adhesins by binding to receptor molecules of different types of human cells in vitro. The M. catarrhalis ubiquitous surface proteins A (UspA1, UspA2H), expressed in most of the clinic isolates, facilitate this pathogen to attach to human cells by binding to host receptor molecules including carcinoembryonic antigenrelated cellular adhesion molecules (CEACAMs), fibronectin, and laminin. More recently, the gene encodes the M. catarrhalis outer membrane protein known as both MID (for Moraxella IgD-binding) and Hag (for as a hemagglutinin) has also been identified in most of clinic M. catarrhalis isolates. Studies shown that different M. catarrhalis strains were isolated from COPD patients experiencing repeated M. catarrhalis-related infectious exacerbations; suggesting a short-term strain-specific protection was developed following each clearance of M. catarrhalis infection. The MID/Hag-reactive antibody has been found in adults with COPD after clearance of M. catarrhalis infection.

Although the genes encode the above putative antigens of M. catarrhalis exist commonly in clinic isolates, the expression of these genes is affected by phase variations. The phase variation, in the 5' untranslated region of the uspA1 gene, results in a significant reduction in the expression of UspA1 protein; whereas the phase variation, in the coding sequence of both UspA2H and MID/Hag proteins, abolishes the expression of UspA2H or MID/Hag due to frame-shift mutations.

In order to perform genome-wide identification of biomarkers for vaccine development, together with Dr. Hansen and Mr. Blick, we have developed the first M. catarrhalis DNA microarray. I have developed the first workable cloning vector (pWW115) for M. catarrhalis. These accomplishments have addressed a serious deficiency in the study of M. catarrhalis genetics.

By using the DNA microarray technology, I study the gene expression in M. catarrhalis cells grown under various conditions relevant to its disease. The initial goals for my study include (1) Identification of biomarkers for M. catarrhalis vaccine development by using DNA microarray to identify bacterial surface proteins whose expression is up-regulated under relevant disease developing conditions; (2) Investigation of genetics of M. catarrhalis pathogenesis in a tissue culture based pathogenesis model; (3) Studying M. catarrhalis elicited inflammatory response by assessing whether the expression of certain M. catarrhalis antigen affects the expression of human inflammatory cytokines in vitro; and (4) Study the regulation of M. catarrhalis virulent genes' expression.


Publications

J Bacteriol 2012 Aug;194(15):4059-68
Bacterium-generated nitric oxide hijacks host tumor necrosis factor alpha signaling and modulates the host cell cycle in vitro.
Mocca B, Wang W

Infect Immun 2012 Mar;80(3):982-95
Use of the chinchilla model for nasopharyngeal colonization to study gene expression by Moraxella catarrhalis.
Hoopman TC, Liu W, Joslin SN, Pybus C, Sedillo JL, Labandeira-Rey M, Laurence CA, Wang W, Richardson JA, Bakaletz LO, Hansen EJ

J Bacteriol 2011 Jun;193(11):2804-13
The Moraxella catarrhalis nitric oxide reductase is essential for nitric oxide detoxification.
Wang W, Kinkel T, Martens-Habbena W, Stahl DA, Fang FC, Hansen EJ

J Bacteriol 2008 Dec;190(23):7762-72
Identification of a repressor of a truncated denitrification pathway in Moraxella catarrhalis.
Wang W, Richardson AR, Martens-Habbena W, Stahl DA, Fang FC, Hansen EJ

Infect Immun 2008 Nov;76(11):5330-40
Modular arrangement of allelic variants explains the divergence in Moraxella catarrhalis UspA protein function.
Brooks MJ, Sedillo JL, Wagner N, Laurence CA, Wang W, Attia AS, Hansen EJ, Gray-Owen SD

Infect Immun 2008 Nov;76(11):5322-9
Moraxella catarrhalis binding to host cellular receptors is mediated by sequence-specific determinants not conserved among all UspA1 protein variants.
Brooks MJ, Sedillo JL, Wagner N, Wang W, Attia AS, Wong H, Laurence CA, Hansen EJ, Gray-Owen SD

Infect Immun 2008 Jun;76(6):2520-30
Moraxella catarrhalis expresses an unusual Hfq protein.
Attia AS, Sedillo JL, Wang W, Liu W, Brautigam CA, Winkler W, Hansen EJ

J Bacteriol 2008 Feb;190(4):1459-72
Moraxella catarrhalis synthesizes an autotransporter that is an acid phosphatase.
Hoopman TC, Wang W, Brautigam CA, Sedillo JL, Reilly TJ, Hansen EJ

Infect Immun 2007 Oct;75(10):4959-71
Metabolic analysis of Moraxella catarrhalis and the effect of selected in vitro growth conditions on global gene expression.
Wang W, Reitzer L, Rasko DA, Pearson MM, Blick RJ, Laurence C, Hansen EJ

Infect Immun 2007 Apr;75(4):2035-45
A UspA2H-negative variant of Moraxella catarrhalis strain O46E has a deletion in a homopolymeric nucleotide repeat common to uspA2H genes.
Wang W, Pearson MM, Attia AS, Blick RJ, Hansen EJ

Plasmid 2006 Sep;56(2):133-7
Plasmid pWW115, a cloning vector for use with Moraxella catarrhalis.
Wang W, Hansen EJ

Plasmid 2006 Jan;55(1):50-7
Development of a shuttle vector for Moraxella catarrhalis.
Wang W, Attia AS, Liu L, Rosche T, Wagner NJ, Hansen EJ

     
 

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