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Overview

Discovery of NeuPSA, a sugar molecule involved in infectious disease and cancer
Our laboratory is working on several projects that developed from studies of a sugar molecule, we have named neuraminic acid-containing polysialic acid or NeuPSA. NeuPSA is a derivative of polysialic acid (PSA), which is the capsular polysaccharide or sugar covering of the neuroinvasive bacterial pathogen Neisseria meningitidis group B (MenB). Only MenB strains that make the sugar can cause disease. It is thought that the PSA capsule allows MenB to evade the immune system. While working on a MenB vaccine based on PSA, we discovered that MenB also make NeuPSA, especially when growing in conditions that simulate infection such as in human blood and serum. At that time, NeuPSA was not known to exist in any organism and we thought it might be unique to MenB. Using antibodies to detect the presence of NeuPSA, we now know that NeuPSA is made by other microbial human pathogens, such as the parasite Leishmania major. It can also be found in specific cells of most human tissues but is made in much larger amounts in many human tumors. A major focus of research in our laboratory is to determine what the function of NeuPSA is and why it is advantageous to pathogenic organisms and cancer cells to make it. We hope that this research will lead to new approaches to preventing or treating diseases, such as meningococcal disease and cancer, where NeuPSA has a role.

 

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. NeuPSA (red) and PSA (green) move to the outside
of the cell only in rosettes (Iovannisci et al, J EuK Micro 2010)

 

NeuPSA expressed on the surface of human melanoma cells (SK-
MEL 28) during cell division. Anti-NeuPSA mAbs can induce
apoptosis in the cells (Steirer and Moe, submitted).

Understanding MenB pathogenesis and developing a vaccine

Currently, there is no vaccine that can prevent MenB disease. However, our studies of NeuPSA and how human serum factors are important for its expression led us to discover a possible mechanism of pathogenesis and a candidate vaccine. It turns out that human serum, in addition to inducing NeuPSA expression in MenB turns on other functions. One example is the ability to bind human antibodies (Ig). This so called non-immune binding of Ig is a known pathogenic mechanism for Gram-positive bacteria such as the Streptococcal bacteria that cause infections like earaches in humans, but was not known to occur in Gram-negative bacteria such as MenB. We identified the Ig binding protein, which is known as TspB. The gene encoding TspB is contained in phage DNA. Phages are viruses that infect bacteria. The discovery is significant because the phage DNA had been linked to the ability of meningococci to cause disease but the reasons why were unknown. Bacteriophage can carry genes that enable bacteria to cause disease. Examples include genes encoding cholera and diphtheria toxins. We identified the segment of the TspB protein involved in Ig binding. We refer to it as the constant region or CR domain. The CR domain is highly conserved among meningococcal strains. Currently, we are investigating whether a TspB-based vaccine can produce antibodies that block non-immune Ig binding and the possibly the mechanism by which TspB facilitates disease. If we are successful, a TspB-based vaccine, because of conservation of the CR domain, would have the potential to protect against all meningococcal strains that cause disease, not just MenB strains.

 

Revised: Tuesday, January 24, 2012 10:27 AM

 

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