Infections due to extracellular bacteria continue to pose a significant global health problem. This is due in large part to the continual emergence of antibiotic-resistant strains. Hence, there exists an urgent need for development of protective vaccines. Immunity is mediated by antibodies to the bacterial polysaccharides (PS) as well as proteins. However, little is known regarding the parameters that mediate in vivo anti-PS and anti-protein responses to intact extracellular bacteria, although such information has relevance to the rational design of immunotherapies for these agents. We have established an in vivo model system for investigating the mechanism of induction of anti-PS and anti-protein Ig isotypes in response to intact Streptococcus pneumoniae. Specifically, the Ig isotype response to the phosphorylcholine (PC) determinant, present on the bacterial cell wall C-PS is studied and compared to the humoral response to a cell wall protein, pneumococcal surface protein A (PspA). We show that induction of optimal anti-PC and anti-PspA responses both require CD4+TCR-a/b+ T cells and B7-dependent costimulation, although memory fails to develop for induction of PC-specific Ig. Of interest, the mechanisms underlying the T cell-dependence of these two responses are distinct. We further show that dendritic cells (DCs) can phagocytose S. pneumoniae upon transfer into naive mice, induce both anti-PC and anti-PspA Ig responses, and the formation of PspA-specific memory. The general aims of this application are to elucidate the mechanisms by which DCs respond to and process an intact extracellular bacterium for induction of both T cell-dependent PC- and PspA-specific Ig isotypes in vivo, and determine the mechanisms underlying the distinct forms of T cell help that stimulate these respective antigen-specific Ig isotype responses. Specifically, we will utilize a number of in vitro and in vivo model systems to determine 1) the parameters that regulate DC activation and antigen presentation in response to R36A, 2) the relative contribution of DC subsets, and 3) the role of DC cytokines and accessory molecules, including CD40, MHC class 11, and Toll-like receptors. In this context, 4) the differential requirements for DC stimulation of T cell help for the anti-PC versus the anti-PspA response will be determined. These data will be the first to establish the detailed parameters that mediate a physiological antigen-specific humoral immune response to an intact extracellular bacterium, including the delineation of the fundamental differences between polysaccharide and protein-specific Ig isotype responses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI049192-01
Application #
6317430
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Klein, David L
Project Start
2001-04-01
Project End
2006-03-31
Budget Start
2001-04-01
Budget End
2002-03-31
Support Year
1
Fiscal Year
2001
Total Cost
$259,350
Indirect Cost
Name
Henry M. Jackson Fdn for the Adv Mil/Med
Department
Type
DUNS #
City
Rockville
State
MD
Country
United States
Zip Code
20817
Saumyaa; Pujanauski, Lindsey; Colino, Jesus et al. (2016) Pneumococcal Surface Protein A Plays a Major Role in Streptococcus pneumoniae-Induced Immunosuppression. J Immunol 196:3677-85
Colino, Jesus; Duke, Leah; Snapper, Clifford M (2014) Autologous albumin enhances the humoral immune response to capsular polysaccharide covalently coattached to bacteria-sized latex beads. Eur J Immunol 44:1433-43
Chen, Quanyi; Snapper, Clifford M (2013) Inflammatory monocytes are critical for induction of a polysaccharide-specific antibody response to an intact bacterium. J Immunol 190:1048-55
Saumyaa; Arjunaraja, Swadhinya; Pujanauski, Lindsey et al. (2013) Immunosuppressive property within the Streptococcus pneumoniae cell wall that inhibits generation of T follicular helper, germinal center, and plasma cell response to a coimmunized heterologous protein. Infect Immun 81:3426-33
Colino, Jesus; Duke, Leah; Snapper, Clifford M (2013) Noncovalent association of protein and capsular polysaccharide on bacteria-sized latex beads as a model for polysaccharide-specific humoral immunity to intact gram-positive extracellular bacteria. J Immunol 191:3254-63
Arjunaraja, Swadhinya; Massari, Paola; Wetzler, Lee M et al. (2012) The nature of an in vivo anti-capsular polysaccharide response is markedly influenced by the composition and/or architecture of the bacterial subcapsular domain. J Immunol 188:569-77
Colino, Jesus; Duke, Leah; Arjunaraja, Swadhinya et al. (2012) Differential idiotype utilization for the in vivo type 14 capsular polysaccharide-specific Ig responses to intact Streptococcus pneumoniae versus a pneumococcal conjugate vaccine. J Immunol 189:575-86
Arjunaraja, Swadhinya; Paoletti, Lawrence C; Snapper, Clifford M (2012) Structurally identical capsular polysaccharide expressed by intact group B streptococcus versus Streptococcus pneumoniae elicits distinct murine polysaccharide-specific IgG responses in vivo. J Immunol 188:5238-46
Colino, Jesus; Chattopadhyay, Gouri; Sen, Goutam et al. (2009) Parameters underlying distinct T cell-dependent polysaccharide-specific IgG responses to an intact gram-positive bacterium versus a soluble conjugate vaccine. J Immunol 183:1551-9
Chattopadhyay, Gouri; Chen, Quanyi; Colino, Jesus et al. (2009) Intact bacteria inhibit the induction of humoral immune responses to bacterial-derived and heterologous soluble T cell-dependent antigens. J Immunol 182:2011-9

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