Infections of the intestinal tract are among the most prevalent causes of disease and death worldwide. In Asia, Africa and Latin America, between 1978 and 1979, 3 to 5 billion cases of diarrhea accounted for 5 to 10 million deaths. The devastating impact of these pathogens has excited interest in host immunity at the intestinal mucosal surface. Much of this interest has focused on the importance of secretory lgA. However, the role of intestinal T lymphocytes in intestinal infections has not been explored. Considering that a sizable portion of the host's total number of T cells is contained in the intestine, little known about the trafficking, memory, or function of these cells after enteric infection. We will examine the importance of intestinal cytotoxic T lymphocytes (CTLs) in protection against enteric infection. Infection of mice with a common intestinal pathogen, rotavirus, will be used to determine 1) the capacity of intestinal and nonintestinal CTLs to protect against rotavirus gastroenteritis, 2) the function, trafficking and memory of rotavirus-specific intestinal and nonintestinal CTLs and CTL precursor after enteric infection, 3) the rotavirus antigens recognized by serotype- specific and crossreactive CTLs, and 4) the T cell receptor proteins which mediate rotavirus-specific CTL activity. We recently found that rotavirus-specific CTLs appear at the intestinal surface after enteric infection. In addition, adoptively-transferred rotavirus-specific Thy1+ CD8+ lymphocytes protect suckling mice against challenge. Rotaviruses are an excellent pathogen for the study of intestinal immunity. First, rotaviruses are the most common cause of infant and childhood gastroenteritis both in the United States and in developing countries. Second, murine rotaviruses, similar to human rotaviruses, replicate in intestinal epithelial cells and are a virulent, natural host pathogen; the pattern of viral replication, diarrhea, and spread found in mice after oral inoculation mimics that found in human disease. Third, we have recently adapted 2 murine rotavirus strains (representing two serotypes) to growth and plaquing in tissue culture. Adaptation of murine rotaviruses to growth in tissue culture allows for an accurate determination of the virus dose used for in vitro and in vivo studies.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Virology Study Section (VR)
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Children's Hospital of Philadelphia
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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
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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
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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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