PspA, a surface protein present on all pneumococci, acts as a virulence factor that can elicit protective antibodies in mice. Surface-attached PspA inhibits the clearance of pneumococci from the blood of mice, probably by inhibiting opsonophagocytosis, although the mechanism of action is not known. The genes encoding PspA from several different strains of the pneumococcus have been sequenced; the protein has a conserved choline-binding domain (involved in the attachment of PspA to the pneumococcal surface) and a variable -helical coiled-coil domain with epitopes that elibcit protective antibodies. A proline-rich domain between the other two domains may allow the protein to span the bacterial cell wall. Immunization of mice with a plasmid containing pspA/Rx1 provided protection against otherwise fatal pneumococcal challenge (one of the first reports of successful genetic immunization against an extracellular bacterial pathogen. The proposed studies will identify those fragments of pspA that are expressed most efficiently in eukaryotic cells. A genetic construct expressing the entire -helical domain has already been tested and it elicits protection against pneumococcal challenge. Additional constructs from within the -helical domain will be made and tested to identify the optimal fragment for use in genetic immunization. Cytokines will also be used to direct the immune system to a Th2 antibody-mediated response. These studies should provide information on those cytokines important in eliciting protective immunity against extracellular bacterial pathogens during genetic immunization, information that might prove more generally useful than just to pneumococcal immunization. The PI will also examine the level of cross protection elicited by genetic immunization with pspA.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI043653-03
Application #
6511058
Study Section
Special Emphasis Panel (ZRG1-BM-2 (02))
Program Officer
Klein, David L
Project Start
2000-04-01
Project End
2005-03-31
Budget Start
2002-04-01
Budget End
2003-03-31
Support Year
3
Fiscal Year
2002
Total Cost
$159,880
Indirect Cost
Name
University of Mississippi Medical Center
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
928824473
City
Jackson
State
MS
Country
United States
Zip Code
39216
Onwubiko, Chinwendu; Shires, Courtney; Quin, Lisa R et al. (2007) Characterization of Streptococcus pneumoniae isolated from children with otitis media. FEMS Immunol Med Microbiol 50:119-25
He, Xiangyun; McDaniel, Larry S (2007) The genetic background of Streptococcus pneumoniae affects protection in mice immunized with PspA. FEMS Microbiol Lett 269:189-95
Quin, Lisa R; Moore 3rd, Quincy C; McDaniel, Larry S (2007) Pneumolysin, PspA, and PspC contribute to pneumococcal evasion of early innate immune responses during bacteremia in mice. Infect Immun 75:2067-70
He, Xiangyun; Thornton, Justin; Carmicle-Davis, Stephanie et al. (2006) Tex, a putative transcriptional accessory factor, is involved in pathogen fitness in Streptococcus pneumoniae. Microb Pathog 41:199-206
Quin, Lisa R; Onwubiko, Chinwendu; Carmicle, Stephanie et al. (2006) Interaction of clinical isolates of Streptococcus pneumoniae with human complement factor H. FEMS Microbiol Lett 264:98-103
Moore, Quincy C; Bosarge, Joseph R; Quin, Lisa R et al. (2006) Enhanced protective immunity against pneumococcal infection with PspA DNA and protein. Vaccine 24:5755-61
Thornton, Justin; McDaniel, Larry S (2005) THP-1 monocytes up-regulate intercellular adhesion molecule 1 in response to pneumolysin from Streptococcus pneumoniae. Infect Immun 73:6493-8
Quin, Lisa R; Carmicle, Stephanie; Dave, Sandhya et al. (2005) In vivo binding of complement regulator factor H by Streptococcus pneumoniae. J Infect Dis 192:1996-2003
Dave, Sandhya; Carmicle, Stephanie; Hammerschmidt, Sven et al. (2004) Dual roles of PspC, a surface protein of Streptococcus pneumoniae, in binding human secretory IgA and factor H. J Immunol 173:471-7
Dave, Sandhya; Pangburn, Michael K; Pruitt, Corunda et al. (2004) Interaction of human factor H with PspC of Streptococcus pneumoniae. Indian J Med Res 119 Suppl:66-73

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