Division of Infectious Diseases, Children's Hospital Boston
300 Longwood Ave
Boston, MA 02115
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Our laboratory studies the acquired and innate immune responses to the common human pathogen, Streptococcus pneumoniae. A major area of interest of the laboratory is the development of alternatives to the expensive and serotype-dependent pneumococcal vaccines. Starting with the mucosal application of killed whole unencapsulated pneumococci, we have identified a novel mechanism of immunity to pneumococcal colonization that may have important implications for the generation of immunity to and development of vaccines against this pathogen: the generation of specific IL-17A-producing CD4+ T cells that greatly reduce the duration and density of nasopharyngeal colonization and may also confer protection against mucosal and invasive disease. Our laboratory is working to further define this mechanism of protection, which appears in addition dependent on neutrophils and independent of antibody. A related effort is also focused on the identification of novel B- and T- cell-dependent antigens, which may lead to novel vaccine candidates. With funding from PATH, and in collaboration with colleagues at the Harvard School of Public Health, Instituto Butantan in Brazil and University of Goteburg, Sweden, our laboratory is pursuing the development of killed, whole cell or species-specific protein vaccines for use in developing countries. We have also recently developed a novel antigen-presenting system that elicits both mucosal and systemic immunity, offering the possibility of generating protection against colonization and invasive disease by various pathogens. We are beginning to explore the feasibility of this type of vaccine strategy for the development of vaccines directed against several other pathogens, which in the future may include Staphylococcus aureus and Mycobacterium tuberculosis.
Another area of interest concerns the interplay between acquired and innate immunity to the pneumococcus. Data from our laboratory show that the recognition of an important toxin of pneumococci--the cholesterol-dependent cytolysin pneumolysin-- occurs via Toll-like receptor 4 (TLR4). More recent data have focused on another component of pneumococcus that potently activates TLR2. Further studies are being performed to determine the specific pathways that are involved in the TLR4- and TLR2-mediated pro-inflammatory activities of these two pneumococcal antigens, the role of these interactions in the development of acquired immunity to pneumococcus, and the possibility of developing novel adjuvants based on these molecules. We are also combining this effort with the whole cell vaccine project, in an attempt to develop an auto-adjuvanted whole cell construct that could be applied mucosally or transcutaneously.
Lu YJ, Gross J, Bogaert D, Finn A, Bagrade L, Zhang Q, Kolls JK, Srivastava A, Lundgren A, Forte S, Thompson CM, Harney KF, Anderson PW, Lipsitch M, Malley R. Interleukin-17A mediates acquired immunity to pneumococcal colonization. PLoS Pathogens, 2008, Sep 19;4(9):e1000159.
Basset A, Thompson CM, Hollingshead SK, Briles DE, Ades EA, Lipsitch M and Malley R. Antibody independent, CD4+ T cell-dependent protection against pneumococcal colonization elicited by intranasal immunization with purified pneumococcal proteins. Infect Imm, 2007 Nov;75(11):5460-4.
Bogaert D, Weinberger D, Thompson C, Lipsitch M, and Malley R. Impaired innate and adaptive immunity to Streptococcus pneumoniae and its effect on colonization in an infant mouse model. Infect Immun. 2009 Apr;77(4):1613-22.
Lu YJ, Forte S, Thompson CM, Anderson PW, Malley R. Protection against pneumococcal colonization and fatal pneumonia by a trivalent conjugate of a fusion protein with the cell wall polysaccharide. Infect Immun. 2009 Mar 2.
For a complete listing of publications click here.
Last Update: 8/1/2012