Richard Malley's 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, Malley and colleagues have identified a novel mechanism of immunity to pneumococcal colonization that may have important implications for the generation of immunity to this pathogen: the generation of specific IL-17A-producing CD4+ T cells that greatly reduce the duration and density of nasopharyngeal colonization. The Malley laboratory is working to further define this mechanism of protection. 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, the Malley laboratory is pursuing the development of killed, whole cell vaccines for use in developing countries.

Another area of interest concerns the interplay between acquired and innate immunity to the pneumococcus. Data from the Malley 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.