Streptococcus pneumoniae is the main cause of acute otitis media, sinusitis, pneumonia, meningitis and bacteremia. Together, these infections cause well over one million deaths worldwide. Rapid spread of penicillin resistant and multiple antibiotic resistant strains of bacteria worldwide pose serious public health threat. The clinical efficacy of 23-valent polysaccharide vaccine is less than ideal, failing to protect individuals at high risk, such as children and the elderly. Although the conjugated 7-valent vaccine, currently licensed in some countries seems promising, it still needs long term clinical evaluation. Moreover, these vaccines are too expensive for the developing world, where the threats for these infections are highest. Our long-term goal is to design a protein based vaccine against pneumococcal infection. A recombinant protein based vaccine has the advantage of being more effective in children and can be produced at low cost. The goal of this proposal is to elucidate the three dimensional structure of a major surface antigen and virulence factor of S. pneumoniae, namely Pneumocoeeal Surface Protein A, (PspA). PspA is a potential vaccine candidate. It is highly immunogenic. Antibodies elicited against PspA are cross-reactive and protective against different strains of pneumococci. It has been used to immunize humans and human anti-PspA antibodies can protect mice from sepsis. PspA inhibits killing of pneumococci by lactoferrin by binding to it. A detailed knowledge of the three dimensional structure of PspA would help us understand the structure function relationship among its epitopes. This knowledge would be extremely valuable for designing effective vaccine based on PspA. Moreover, structure of PspA with human lactoferrin would allow designing novel strategies to block PspA-lactoferrin interaction. Towards these goals, the specific aims of this proposal are: 1) Determine the crystal structure of PspA. 2) Determine the structure of PspA-lactoferrin complex. [unreadable] [unreadable]