Associate Physician, Department of Medicine
Brigham and Women's Hospital

mbaron@partners.org

Group B Streptococcal Surface Proteins

Dr. Baron's major research focus has been the interaction of host cells with surface proteins of group B streptococci (Streptococcus agalactiae, GBS), a pathogen that infects neonates, peripartum women, and immunocompromised adults. Up to 54% of the general population are colonized with GBS in the gastrointestinal/gynecological/skin regions. Of particular interest are the identification of vaccine antigens and of factors determining whether the GBS-host interaction results in colonization or in invasive infection.

One protein, the beta C protein, found on the surface of some strains of GBS, elicits protective immunity, raising hope that this protein might make an effective vaccine antigen. Through further study, however, we have found that naturally-acquired human antibodies recognizing similar protein regions may not protect against GBS disease, despite similar binding affinity. Antigenic variation in the beta C protein among GBS strains and/or within a single strain at different points in time may explain the difference in protective efficacy between naturally-acquired human antibodies and vaccine-induced animal antibodies specific for this protein.

Another surface protein, the alpha C protein, is the prototype for a family of Gram-positive surface proteins, the alpha-like proteins (Alps), found on most GBS strains and also on the surface of other Gram-positive bacterial species. Alps share sequence homology and common structural elements. Despite the fact that these proteins may vary in size due to gene truncation within the repeat region, Alps elicit protective antibody in both adult and neonatal mouse models of GBS sepsis. Deletion of the gene encoding the alpha C protein attenuates the virulence of GBS in the neonatal mouse model. In vitro, the deletion strain both enters epithelial cells and crosses layers of these cells less effectively than the wild-type strain.

One current goal is to better understand the molecular events in the interaction of Alps with host cells. We have found that alpha C protein binds to host cell surface glycosaminoglycan and enters epithelial cells, by a mechanism requiring actin polymerization and mediated by Rho GTPases. We have identified a region of the alpha C protein that binds to glycosaminoglycan, and have shown recently that elimination of this activity leads to decreased bacterial invasion of host cells. Such data suggest that the interactions between Alps and host cells may facilitate the transition from GBS colonization to invasive GBS infection.

Host Factors Interacting with Bacterial Structures

We are developing an animal model of infection in which to study the Alp-host cell interactions in more detail. We plan to further characterize the host cell receptor and the detailed interactions linking alpha C protein-glycosaminglycan binding to actin rearrangements. In addition, we will use the new infection model to identify additional host factors that interact with bacterial virulence factors and thereby determine the outcomes of infection.

Lachenauer CS, Baker CJ, Baron MJ, Kasper DL, Gravekamp C, Madoff LC. Quantitative determination of immunoglobulin G specific for group B streptococcal beta C protein in human maternal serum. J Infect Dis. 2002 Feb 1;185(3):368-74. Epub 2002 Jan 17. [abstract]

Bolduc GR, Baron MJ, Gravekamp C, Lachenauer CS, Madoff LC. The alpha C protein mediates internalization of group B Streptococcus within human cervical epithelial cells. Cell Microbiol. 2002 Nov;4(11):751-8. [abstract]

Baron MJ, Bolduc GR, Goldberg MB, Aupérin TC, Madoff LC. Alpha C protein of group B Streptococcus binds host cell surface glycosaminoglycan and enters cells by an actin-dependent mechanism. J Biol Chem. 2004 Jun 4;279(23):24714-23. Epub 2004 Mar 23. [abstract]

Aupérin TC, Bolduc GR, Baron MJ, Heroux A, Filman DJ, Madoff LC, Hogle JM. Crystal structure of the N-terminal domain of the group B streptococcus alpha C protein. J Biol Chem. 2005 May 6;280(18):18245-52. Epub 2005 Mar 6. [abstract]

Baron MJ, Filman DJ, Prophete GA, Hogle JM, Madoff LC. Identification of a glycosaminoglycan-binding region of the alpha C protein that mediates entry of group B streptococci into host cells. J Biol Chem. 2007 Jan 26; [Epub ahead of print]. [abstract]