Streptococcus pneumoniae (Pn)is an extracellular bacterium that is a major cause of global morbidity and mortality. Systemic adaptive immunity to Pn is mediated by antibody, especially IgG specific for the capsular polysaccharide (PS),but also for bacterial proteins. Our long-term goal is to elucidate the cellular mechanismsthat underlie the distinct differences that exist between in vivo anti-PSand anti-protein Ig responses to intact Pn, as a prerequisite to the development of improved vaccines.In contrast to the current dogma, based on using purified PS antigens, that IgG anti-PS responses are T cell-independent, we demonstrated that the IgG anti-PS response to intact Pn is heavily dependent on CD4+ T cells but nevertheless, still exhibits striking differences in kinetics, generation of memory, and the functional roles of dendritic and T cells relative to the co-induced anti-protein response. In light of these data, the central hypothesis that underlies our proposed research is that differential B cell receptor signaling and/or involvement of functionally distinct B cell subsets are the key parametersthat distinguish physiologic anti-PS and anti-protein Ig responses. We will demonstrate that these parameters differentially impact on 1) the temporal compartmentalization of responding B cells within the spleen, and 2) the cellular interactions of the responding B cells with other immune cell types. As a result we will provide a mechanistic basis that will elucidate the observed differences in anti-PS and anti-protein responses.
The specific aims are to: 1. Determine the nature and relationships of B cell and dendritic cell subsets, and CD4+ T cells that differentially mediate in vivo anti-PS and anti-protein Ig isotype responses to systemic immunization with intact Pn. We will utilize high speed electronic cell sorting and adoptive transfer of wild-type and genetically altered immune cells combined with ELISPOT and ELISA analyses of antigen-specific Ig isotype production to accomplish thisaim. 2. Determine the mechanism by which B cells, DCs,and CD4+ T cells differentially orchestrate anti-PS and anti-protein responses within a spatiotemporal context. We will utilize B cells from BCR knock-in mice with Ig specificity for Pn-derived PS or protein antigens and T cells from CD4+ TCR transgenic mice with specificity for a Pn-derived protein to accomplish this aim.These cells will be used to conduct in vitro functional studies and confocal microscopic analyses of splenic tissue sections post-immunization. These studies are the first to systematically determine the mechanisms that distinguish anti-PS from anti-protein responses to an intact bacterium and provide novel basic immunologic insights with direct relevanceto the development of anti-bacterial vaccines.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Immunity and Host Defense Study Section (IHD)
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Khambaty, Farukh M
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Henry M. Jackson Fdn for the Adv Mil/Med
United States
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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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