Harvard Catalyst Profiles

Our research encompasses identification of the molecular basis for the interactions of major human and animal bacterial pathogens with mammalian hosts, with the primary goal being identification of surface antigens eliciting protective innate and adaptive immunity that also contribute to the organism’s virulence. As a result of our interest in a conserved surface polysaccharide, poly-N-acetyl glucosamine, (PNAG), which we and others have found is synthesized by a diverse range of bacterial species. We now are investigating how this molecule plays a role in virulence and immunity to numerous pathogens, including Staphylococcus aureus, S. epidermidis, E. coli, Y. pestis, K. pneumoniae, B. cenocepacia and others. Recent testing of vaccines to PNAG in economically important animals challenged with natural pathogens has shown high levels of protection can be induced by this vaccine.

Newer investigations have focused on how the microbiota, the trillions of organisms inhabiting human bodies, impact the development of diseases traditionally not associated with an infectious basis. By using antibodies specific to the broadly-expressed PNAG antigen to detect microbial factors in tissues from humans that died of diseases such as Alzheimer’s disease and type 1 diabetes, we have found evidence for microbial cells and fragments in these tissues, suggesting that microbes are driving the destructive inflammatory response leading to clinical disease. Importantly, in mouse models of Alzheimer’s disease and diabetes we find that vaccinating against PNAG prevents the development of cognitive decline in Alzheimer’s and onset of hyperglycemia in otherwise diabetic mice. These investigations are expanding to get a better understanding of how the microbiota contributes to the tissue destruction underlying the pathology of such diseases.

The vaccine to PNAG was also successful in protecting horse foals from Rhodococcus equi infections following vaccination of pregnant mares and pigs against a virulent respiratory pathogen, Actinobacillus pleuropneumoniae. Advancing the study of PNAG expression and vaccine efficacy in economically important animals and pets is an additional focus of the lab’s work.

In addition, our research efforts have also focused on Pseudomonas aeruginosa, a major nosocomial pathogen and cause of serious infections in the setting of cystic fibrosis. Since P. aeruginosa is one of the few pathogenic microbes that does not produce the PNAG antigen we have also generated and are commercializing with a partner company a fully human IgG 1 monoclonal antibody to a comparable P. aeruginosa surface antigen, termed alginate, with the eventual goal of testing in CF patients for prevention of P. aeruginosa infection.