Professor of Medicine (Microbiology and Molecular Genetics)
Brigham and Women's Hospital
181 Longwood Ave
Boston MA 02115
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.
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to make corrections and additions.
Sep 1, 2021 - Aug 31, 2022
Harvard Medical School/Harvard Catalyst
Role of the Borrelia surface polysaccharide PNAG in virulence and immunity in Lyme disease.
Role Description: This study will look at the role of the Borrelia surface polysaccharide PNAG in virulence and immunity in Lyme disease.
Role: Principal Investigator
Aug 30, 2021 - Aug 29, 2024
Preventing Alzheimer’s Disease Cognitive Decline by Vaccinating Against the Microbiota-Driven Neural Tissue Destructive Inflammatory Response
Role Description: We hypothesize that the persistence of microbiota-derived cells or fragments that are closely associated with beta-amyloid (Abeta) deposits in the brains of deceased AD individuals, are providing the inflammatory stimuli resulting in neural tissue destruction and cognitive impairment. Our goal is to validate this with human and mouse brain tissues as well as determine in immunotherapies targeting the conserved microbial surface polysaccharide, poly-N-acetyl glucosamine (PNAG), can prevent cognitive decline in a murine model of AD.
Role: Principal Investigator
Jul 1, 2021 - Jun 30, 2022
Football Players health Study
Role of Poly-N-Acetyl-Glucosamine (PNAG) in brain inflammation and functional outcome after closed head injury in mice
Role Description: The major goal of this study is to demonstrate that microbiota-derived PNAG-containing microbial fragments contribute to the CNS inflammation associated with cognitive impairment in TBI
Role: Co-Principal Investigator
Jun 15, 2021 - Jun 14, 2022
Brigham and Women's Hospital
Preventing Alzheimer’s Disease Cognitive Decline by Targeting the Microbiota-Driven Neural Tissue Destructive Inflammatory Response with a Monoclonal Antibody (MAb) Therapy Ready for Human Clinical Trials
Role Description: The major goal is to evaluate a fully human monoclonal antibody (MAb) for efficacy in preclinical mouse moels of Alzheimer's Disease. This is a different strain of AD mouse from the one proposed in the Cure Alzheirmer’s Fund application with different genetic basis for development of pathology and cognitive and behavioral changes.
Mar 1, 2018 - Feb 29, 2020
Efficacy of Maternal Immunization Against PNAG to Protect Newborn Foals Against Rhodococcus equi Pneumonia
Role Description: Our objective is to develop a vaccine that can protect foals against pneumonia caused by natural infection with R. equi under field conditions. Our 1st hypothesis (H1) is that maternal vaccination against PNAG can protect foals against intrabronchial infection with virulent R. equi during the 1st week of life. Our 2nd hypothesis (H2) is that this protection is correlated with the transfer of antibodies against PNAG in plasma that fix complement and mediate opsonophagocytic killing of R. equi in macrophages.
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