gregory R. moe, phd

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Phone: 510-450-7641

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Overview

Discovery of de-N-acetyl polysialic acid (dPSA), a sugar molecule involved in infectious disease and cancer
Our laboratory is working on several projects that developed from our discovery of dPSA. Polysialic acid is the capsular polysaccharide covering of the neuroinvasive bacterial pathogens Neisseria meningitidis group B (MenB) and E. coli K1 and modifies a few proteins involved in eukaryotic cell-cell interactions. While working on a MenB vaccine based on PSA derivatives, we discovered that MenB (and E. coli K1) also make dPSA. At that time, dPSA was not known to exist in any organism and we thought it might be unique to MenB. Using antibodies to detect the presence of dPSA, we now know that dPSA is made by other microbial human pathogens, such as the parasite Leishmania major, where we showed that it is involved in the formation of promastigote rosettes in a previously unrecognized sexual cycle. It can also be found inside specific cells of many human tissues but is abnormally overexpressed and present on the surface of cancer cells. A major focus of research in our laboratory is to determine what the function of dPSA is and why it is advantageous to pathogenic organisms and cancer cells to make it. We showed that anti-dPSA monoclonal antibodies (mAbs) have antibody-dependent cytotoxicity by inducing apoptosis in human melanoma, acute lymphocytic leukemia, and neuroblastoma cell lines. The mAbs also alter melanoma cell morphology, adhesion and migration in culture. Recently, we found that an anti-dPSA mAb can inhibit tumor progression in animal models of melanoma, basal cell carcinoma, and neuroblastoma. We have identified a protein directly modified with dPSA or associated with dPSA that is already known to have a central role in many human cancers and directly affecting multiple processes that are the hallmarks of cancer. The protein identified is also a focus for cancer diagnostics and a target of therapeutic approaches to treating or preventing cancer. dPSA-based vaccines, mAbs, mAb derivatives, chimeric antigen receptor T cells, and mechanism based inhibitors of PSA de-N-acetylase offer novel approaches to targeting an invariant carbohydrate antigen uniquely surface expressed in a wide variety of cancers. We hope that this research will lead to new approaches to preventing or treating diseases, such as meningococcal disease and cancer, where dPSA has a role in disease.

dPSA

 

Electron micrograph of Neisseria meningitidis group B (MenB)
bacteria showing blebbing of outer membrane and capsular
polysaccharide (PSA). Photo: UK PHS, Porton Down

 

Laser scanning confocal micrograph of Leishmania major parasites
clustered in a rosette. dPSA (red) and PSA (green) move to the outside
of the cell only in rosettes (Iovannisci et al, J EuK Micro 2010)

 

dPSA expressed on the surface of human melanoma cells (SK-
MEL 28) during cell division. Anti-dPSA mAbs can induce
apoptosis in the cells (Steirer and
Moe, 2011. PLoS ONE,6:e27249)

MenB vaccine development, mechanisms of pathogenesis and the effect of vaccine elicited antibodies on meningococcal colonization
Currently, there is no vaccine that can prevent disease caused by all strains of MenB. Recently licensed MenB vaccines based on meningococcal complement factor H binding protein (FHbp) are limited by poor immunogenicity, relatively narrow range of strains covered, and potential safety concerns about eliciting auto-reactive anti-FH. We are working to develop a more immunogenic, broadly protective, and safer vaccine based on FHbp that does not bind FH that is overexpressed in native outer membrane vesicles. In addition, we are investigating the effect of antibodies elicited by meningococcal vaccines in cell culture and animal models of meningococcal colonization. This work has provided new insights about how vaccines, such as capsular polysaccharide protein-conjugate vaccines, elicit antibodies that not only protect the vaccinated individual but also limit transmission to the un-vaccinated.
Finally, a gene carried by a bacterial virus (bacteriophage) coding for meningococcal T and B cell stimulating protein B (TspB) had been identified as being causally associated with invasive meningococcal disease. We determined that TspB functions as an immunoglobulin (Ig) and DNA binding protein, which provides protection against immune mechanisms in human blood that would normally clear the bacteria. Ig-binding proteins are common virulence factors in Gram-positive but are rare in Gram-negative bacterial pathogens. We are investigating the role of TspB in meningococcal pathogenesis and whether a vaccine based on TspB can block transmission of the virus harboring tspB genes to non-invasive strains as a means of eliminating the spread of pathogenic meningococci.

Tsp biofilm

 

Revised: Monday, September 26, 2016 11:37 AM

UCSF

 

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