Research in the Goldberg Lab

Recent Publications

The major focus of our laboratory is in the investigation of strategies used by bacteria to cause diseases in humans. We study various bacteria and their factors especially surface polysaccharides and other potential adhesions, and assess their effect on the virulence and physiology of the bacterium, as well as on host cells. Our general approach is to perform genomic analysis, construct, and characterize bacterial mutants, and monitor these for relevant phenotypic and genotypic characteristics and in in vivo and in vitro models of infection. The long-term goal of this work is to devise rational methods to the disrupt virulence and promote clearance of infecting bacteria.

Pseudomonas aeruginosa is a Gram-negative bacterium that is ubiquitous in the environment. This bacterium can act as an opportunistic pathogen, causing acute infections in patients whose health is compromised and chronic pulmonary infections, which are the major cause of death, in patients with cystic fibrosis (CF). P. aeruginosa possesses a wide array of factors associated with virulence. One of these is lipopolysaccharide (LPS), a component of the Gram-negative cell surface. P. aeruginosa strains found in acute infections and in the environment produce LPS that is smooth, with many long O-side-chain antigens attached to the LPS core. However, P. aeruginosa isolates from chronic pulmonary infections in CF patients tend to produce LPS that is rough, with short O antigen side chains or none. One of our goals is to elucidate the nature of the mutations in the O antigen locus that result in the LPS-rough phenotype in P. aeruginosa isolates from patients with CF as well as the regulation of this virulence factor. Another is to use both genomic and proteomic approaches to study the genes and proteins that are altered during the conversion from the initial infection to the chronic infection. The long-term goals are to identify novel genes that may be unique to certain stages of infection and target these for vaccine development. In addition we are trying to develop a recombinant LPS O antigen-based vaccines against acute and chronic P. aeruginosa infections.

Burkholderia cepacia complex (Bcc) is another group Gram-negative opportunists that can cause lung infections in CF patients. Unlike P. aeruginosa, which causes a chronic long-term infection in this setting, Bcc can cause acute pulmonary deterioration that can include bacteremia, necrotizing pneumonia, sepsis and death, a condition referred to as "cepacia syndrome". This deadly outcome has been shown to occur in approximately 20% of Bcc-colonized CF patients. We are interested in defining the potential adhesin molecules of Bcc that are important for the initial interactions between this bacterium and the host. Our work has focused on the cell surface polysaccharides, LPS, flagella, cable pili, and a 22 kD adhesin. The effect of mutations in the genes encoding these factors has revealed their role in the infectious process. We are currently investigating how these factors are synthesized and regulated. This information will allow us to develop strategies and therapeutics to block the adherence of Bcc, thereby inhibiting a critical step in the pathogenesis of these infections in CF.

Burkholderia mallei and Burkholderia pseudomallei are category B priority pathogens that cause glanders and melioidosis, respectively. Our approach includes the identification and cloning of genes encoding enzymes required for the production of polysaccharides and immunodominant protective proteins of these agents. We do not currently have the facilities to work with these biothreat agents directly, however, studies using genomic and immunological analyses to develop recombinant vaccines to these agents and the immunizations with these antigens can be performed in our BSL-2 facilities. Experiments requiring BSL-3 and ABSL-3 facilities are currently being performed in collaboration at other institutions.