Abstract
Mice are exceedingly sensitive to intra-peritoneal (IP) challenge with some virulent pneumococci (LD50 = 1 bacterium). To investigate how peripheral contact with bacterial capsular polysaccharide (PS) antigen can induce resistance, we pulsed bone marrow dendritic cells (BMDC) of C57BL/6 mice with type 4 or type 3 PS, injected the BMDC intra-foot pad (IFP) and challenged the mice IP with supra-lethal doses of pneumococci. We examined the responses of T cells and B cells in the draining popliteal lymph node and measured the effects on the bacteria in the peritoneum and blood. We now report that: 1) The PS co-localized with MHC molecules on the BMDC surface; 2) PS-specific T and B cell proliferation and IFNγ secretion was detected in the draining popliteal lymph nodes on day 4; 3) Type-specific resistance to lethal IP challenge was manifested only after day 5; 4) Type-specific IgM and IgG antibodies were detected in the sera of only some of the mice, but B cells were essential for resistance; 5) Control mice vaccinated with a single injection of soluble PS did not develop a response in the draining popliteal lymph node and were not protected; 6) Mice injected with unpulsed BMDC also did not resist challenge: In unprotected mice, pneumococci entered the blood shortly after IP inoculation and multiplied exponentially in both blood and peritoneum killing the mice within 20 hours. Mice vaccinated with PS-pulsed BMDC trapped the bacteria in the peritoneum. The trapped bacteria proliferated exponentially IP, but died suddenly at 18–20 hours. Thus, a single injection of PS antigen associated with intact BMDC is a more effective vaccine than the soluble PS alone. This model system provides a platform for studying novel aspects of PS-targeted vaccination.
Highlights
The protective immune response to a potentially pathogenic agent is a complex phenomenon involving activations of innate and adaptive immune cells in response to target antigens, the elaboration of effector mechanisms, and effects on the pathogen – all progressing at specific times and in different anatomic compartments in the host body
We previously reported that resistance to a lethal challenge with Pn could be induced by vaccination with a macrophage line or with bone marrow-derived dendritic cells (BMDC) that had been pulsed with the PS of the challenge Pn serotype
The experiments described here were undertaken to obtain a comprehensive look at the induction of resistance to lethal Pn challenge induced in mice by intra footpad injection of PS-pulsed BMDC
Summary
The protective immune response to a potentially pathogenic agent is a complex phenomenon involving activations of innate and adaptive immune cells in response to target antigens, the elaboration of effector mechanisms, and effects on the pathogen – all progressing at specific times and in different anatomic compartments in the host body. The pathogenicity of Streptococcus pneumoniae has been attributed to the PS antigen of the bacterial surface [1,2]. A new generation of pneumococcal vaccines has been designed in which the PS antigen is conjugated to a carrier protein immunogenic for helper T cells [8]. There have been few studies of the possible role of innate mononuclear antigen presenting cells like dendritic cells (DC) and macrophages in the activation of the immune response to the PS
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