The in vitro and in vivo biological activity of a protective human IgM monoclonal antibody to Streptococcus pneumoniae
Fabrizio, Kevin R.
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Streptococcus pneumoniae currently remains the most common etiologic agent of community-acquired pneumonia in the United States and in other countries. In humans and murine models, pneumococcal disease is often associated with an exuberant host response, characterized by tissue inflammation and high levels of cytokines and chemokines. As such, modalities that can modulate host inflammation in addition to inducing bacterial clearance may hold promise for treating pneumococcal disease. Currently, in the United States and many other parts of the world, pneumococcal capsular polysaccharide- (PS) based vaccines are used to prevent pneumococcal disease in adults and children. However, whether they elicit host responses that modulate the inflammatory response has not been a major focus of studies of vaccine efficacy. The goal of this thesis project was to determine the host requirements for the efficacy of a human monoclonal IgM (A7) to serotype 3 (ST3) and the mechanism by which it mediates protection against pneumococcal disease in a sepsis model.;A7 is a non-opsonic MAb that protects against lethal intraperitoneal challenge with ST3. We found that A7-mediated efficacy did not require B or T cells. In normal mice, its efficacy was associated with a significant decrease in blood and tissue bacterial burdens, a decrease in blood and splenic cytokines and chemokines and higher numbers of circulating leukocytes and lymphocytes compared to control mice. The efficacy of A7 was also found to depend on macrophages. Compared to macrophage-sufficient controls, depletion of peritoneal macrophages resulted in higher levels of tissue and blood bacterial burdens and cytokines/chemokines and death. A7 was also found to induce bacterial agglutination in vitro and co-administration of ST3 with the same amount of MAb that protected in vivo did not induce lethal disease.;Taken together, these findings suggest that A7 mediates protection against pneumococcal disease and sepsis by a mechanism that depends on macrophages and results in a reduction in bacterial dissemination and host inflammation. The mechanism that governs this effect has yet to be identified.
- Theses and Dissertations