Whereas protection following natural infection with systemic viruses (such as measles, mumps, rubella, or varicella) is usually life-long and complete (1), protection following infection with mucosal viruses (such as rotavirus, influenza virus or respiratory syncytial virus) is usually short-lived and incomplete (2). Two observations might explain these differences. First, antibody-secreting cells (ASC) at mucosal surfaces after natural infection or immunization (primary ASC) are short-lived (3). Second, the time required for generation of secondary ASC derived from memory B cells is often longer than the incubation periods of most mucosal pathogens. Therefore, development of vaccines that provide long-lived and complete protection against mucosal pathogens will depend upon either prolonging primary ASC after immunization or hastening the onset of secondary ASC after challenge. To enhance virus-specific mucosal immune responses, we recently developed a system of microencapsulation based on the ionic linkage of aqueous polymers and aqueous amines (10). We found that microcapsules enhance the magnitude of primary and secondary rotavirus-specific ASC and enhance protection against rotavirus challenge. Although the mechanism by which microcapsules enhance protective virus-specific immune responses remains unclear, we found that microcapsules containing rotavirus might select for antigen-presenting cells (APC) different from and perhaps more efficient that those involved during natural infection. Using microencapsulated and unencapsulated preparations of rotavirus, we will determine whether APC type (i.e. dendritic cells, macrophages, B cells, or intestinal epithelial cells) alters primary or secondary ASC responses. In addition, by biologically or chemically modifying microcapsules, we will determine whether alteration in the type of APC recruited during mucosal infection, or alteration in the kinetics of antigen presentation, modifies protective immune responses. The availability of microencapsulated virus provides a unique opportunity to understand the relationship between APC and protective mucosal immune responses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI026251-15
Application #
6840423
Study Section
Experimental Virology Study Section (EVR)
Program Officer
Berard, Diana S
Project Start
1990-01-01
Project End
2005-12-31
Budget Start
2005-01-01
Budget End
2005-12-31
Support Year
15
Fiscal Year
2005
Total Cost
$437,500
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Moser, C A; Offit, P A (2001) Distribution of rotavirus-specific memory B cells in gut-associated lymphoid tissue after primary immunization. J Gen Virol 82:2271-4
Macartney, K K; Baumgart, D C; Carding, S R et al. (2000) Primary murine small intestinal epithelial cells, maintained in long-term culture, are susceptible to rotavirus infection. J Virol 74:5597-603
Brubaker, J O; Patil, R T; Speaker, T J et al. (2000) A quantitative luminescence assay for measuring cell uptake of aqueous-based microcapsules in vitro. J Immunol Methods 237:85-93
Coffin, S E; Clark, S L; Bos, N A et al. (1999) Migration of antigen-presenting B cells from peripheral to mucosal lymphoid tissues may induce intestinal antigen-specific IgA following parenteral immunization. J Immunol 163:3064-70
Moser, C A; Speaker, T J; Offit, P A (1998) Effect of water-based microencapsulation on protection against EDIM rotavirus challenge in mice. J Virol 72:3859-62
Brown, K A; Offit, P A (1998) Rotavirus-specific proteins are detected in murine macrophages in both intestinal and extraintestinal lymphoid tissues. Microb Pathog 24:327-31
Moser, C A; Cookinham, S; Coffin, S E et al. (1998) Relative importance of rotavirus-specific effector and memory B cells in protection against challenge. J Virol 72:1108-14
Coffin, S E; Offit, P A (1998) Induction of mucosal B-cell memory by intramuscular inoculation of mice with rotavirus. J Virol 72:3479-83
Coffin, S E; Moser, C A; Cohen, S et al. (1997) Immunologic correlates of protection against rotavirus challenge after intramuscular immunization of mice. J Virol 71:7851-6
Moser, C A; Speaker, T J; Offit, P A (1997) Effect of microencapsulation on immunogenicity of a bovine herpes virus glycoprotein and inactivated influenza virus in mice. Vaccine 15:1767-72

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