Richard Malley is exploring the possibility of an alternative to the expensive capsular-based pneumococcal vaccines through eliciting immunity to species antigens of pneumococcus. Building on the success with mucosal applicaton of killed whole unencapsulated pneumococci, Malley and colleagues are woking to further define the mechanisms underlying the protection generated by immunity to several species' antigens to pneumococcus. In particular, they are using various knockout mutants of pneumococci to identify the antigen(s) responsible for this protection. Using various animal models, it has been demonstrated that immunized animals are extremely resistant to nasopharyngeal colonization with encapsulated pneumococci. These findings raise the possibility of generating herd immunity to pneumococci.

Another area of interest, tied to the research above, 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). Like Gram-negative bacteria, major components of the Gram-positive bacterial cell wall employ CD14 for immune recognition. Previously, researchers have demonstrated that co-expression of CD14 and TLR2 results in the recognition of S. pneumoniae. Studies by Dr. Malley and colleagues have demonstrated that recognition of pneumolysin via TLR4 is a critical component in the innate resistance against pneumococcal colonization and invasive disease. Further studies are being performed to determine the specific pathways that are involved in the TLR4-mediated pro-inflammatory activity of pneumolysin and the role of this interaction in the development of acquired immunity to pneumococcus.