Protective immunity to Streptococcus pneumoniae

Streptococcus pneumoniae causes severe diseases in millions and yearly kills about 1 million children. In high income countries, the elderly is the most affected group. Despite their effectiveness, current pneumococcal vaccines do not target all S. pneumoniae. The limited coverage, compounded by the ability of S. pneumoniae to exchange DNA and thereby escape recognition by the current vaccines, have led to efforts to find novel vaccines. In this project, we examine whether Streptococcus mitis, a close relative of S. pneumoniae found in the normal human microbiota, can induce protection against S. pneumoniae. This is based on the hypothesis that the high similarity between the two species generate cross-reactive responses with potential application in vaccine development. We found that antisera raised against S. mitis reacted with multiple proteins of virulent S. pneumoniae strains. The opposite was also true, in that antisera against S. pneumoniae could also recognize various proteins on S. mitis. Furthermore, humans intranasally inoculated with S. pneumoniae in a pneumococcal model of human carriage exhibited increased serum antibodies against S. mitis. Using an on-chip protein microarray representing a number of selected membrane and extracellular S. pneumoniae proteins, we identified choline-binding protein D (CbpD), cell division protein (FtsH), and manganese ABC transporter or manganese-binding adhesion lipoprotein (PsaA) as common antibody targets. In interactions with oral mucosal keratinocytes, S. mitis activated a key regulator of host immune responses in the cells, and important feature that may confer S. mitis with the ability to tight regulate inflammation. In interactions with monocytes, S. mitis triggered increased transcription of a variety of chemotactic factors and cytokines important in the initiation of inflammation and induction of Th17 responses. Further experiments revealed that vaccination with S. mitis in a mouse model could indeed boost production of Th17 cells, as well as IgG and IgA antibodies. As for any candidates for live-bacteria vaccines, safety and efficiency are key issues. Thus, detailed characterization of mechanisms by which these bacteria interact with the host is of high relevance, particularly under immune suppressive conditions. This poses a challenge, since S. mitis is notoriously difficult to transform, thus precluding the general use of genetic techniques of unique value in microbial studies to characterize mechanisms used by S. mitis to interact with the host. By optimizing growth conditions and using large stretches of DNA as donors, we were able to overcome this limitation in representative strains of S. mitis. Such tools have been used in our studies to characterize important interactions not only with the host, but also those between S. mitis and S. pneumoniae. In a mouse model of lung infection, we were able to demonstrate that intranasal immunization with S. mitis protected against pneumococcal lung infection. Although expression of the S. pneumoniae capsule was not required for protection, a hybrid S. mitis strain constructed in the laboratory to express the S. pneumoniae capsule was superior in inducing protection. Overall, the present results support the potential of S. mitis to confer broad protective immunity to S. pneumoniae. Further investigations are already being pursued to identify S. mitis natural isolates with optimal protective and safe features for use in human feasibility studies.

Despite the availability of pneumococcal vaccines, Streptococcus pneumoniae inflicts a severe socioeconomic burden on people worldwide. This accentuates the need for novel prophylactic strategies. We took advantage of Streptococcus mitis, a natural human colonizer that shares immunogenic characteristics with S. pneumoniae, to induce protection against pneumococcal infection. Using an on-chip protein microarray, we identified choline-binding protein D (CbpD), cell division protein (FtsH), and manganese ABC transporter or manganese-binding adhesion lipoprotein (PsaA) as common targets of S. mitis and S. pneumoniae IgG antibodies. Intranasal immunization of mice with S. mitis or its genetically engineered mutant expressing the pneumococcal capsule conferred protection against S. pneumoniae lung infection, which may have important implications for developing commensal-based vaccines against various pathogens, including S. pneumoniae.

In this project, we want to examine immune cross-recognition responses that may improve current vaccination strategies against pneumococcal infections. Streptococcus pneumoniae causes severe diseases in millions and yearly kills about 1 million children. In high income countries, the elderly are the most affected with invasive pneumococcal diseases. Despite their effectiveness, current vaccines against S. pneumoniae target only selected capsular serotypes. The high cost and limited serotype coverage, compounded by serotype replacement, have led to efforts to find novel approaches that target all strains of S. pneumoniae. It was recently found that experimental human carriage of S. pneumoniae resulted in mucosal and systemic immunological responses that conferred protection against re-colonization and invasive pneumococcal disease. On this background, we want to examine if exposure to selected commensal streptococci induces a state of immunity protective against pneumococcal carriage and infections. This would be the first stage to pave the way to new strategies addressing the limitations of current pneumococcal vaccines.