Most infections involve mucous membranes, either as the actual site of infection or as the portal of entry into the body. This Program Project is designed to investigate the nature, significance, and prophylactic and therapeutic potential of the mucosal immune response to infectious pathogens. The overall goals are to gain increasing insights into: mechanisms of defense mediated by IgA, therapeutic efficacy of passive administration of specific IgA antibody, development of new vaccines to prevent selected mucosal infections, and certain immunopathological complications of the mucosal immune response to infection. The research, to be performed by investigators with both basic science and clinical backgrounds, will deal with infections of the respiratory and gastrointestinal tracts caused by viruses, bacteria, and protozoa. The four projects will focus on animal models of important human diseases and the role of mucosal IgA antibodies in host defense. The relevant human diseases are amebiasis, H. pylori gastritis (thought to account for most cases of peptic ulcer disease), and diseases associated with mucosal viral infection, including IgA nephropathy. While the traditional protective function of mucosal IgA has been considered to act as an immune exclusion barrier, a newly proposed function based on studies in vitro, namely neutralization of viruses inside mucosal epithelial cells, will now be investigated in vivo. The first project, on amebiasis, seeks to exploit components of E. histolytica that are promising candidates for vaccine antigens, notably a galactose-inhibitable adherence protein that is critical to pathogenesis. This research will take advantage of a new baboon model of intestinal amebiasis. The second project, on Helicobacter-induced gastritis, will also investigate promising candidate vaccine antigens, including urease. The research will exploit the recently available model of H. felis infection of germ-free mice. In the third project, the ability of IgA antibodies to neutralize viruses intracellularly will be studied in infections of the respiratory tract and liver. For respiratory infection, Sendai virus, a natural pathogen of mice and a close relative of the parainfluenza viruses that cause human respiratory illnesses, will be used; the studies in hepatitis will employ mouse hepatitis virus, a coronavirus similar to human coronaviruses. Intracellular neutralization of virus by IgA monoclonal antibodies will be assessed in tracheal epithelial cells and hepatocytes in severe combined immunodeficient (SCID) mice. Since IgA nephropathy, the most common form of glomerulonephritis, is associated temporally with upper respiratory illness, the fourth project will seek to develop a mouse model that is induced by a respiratory viral (Sendai) infection and that mimics the essentials of the human disease. Those features of the infection and of the host response that lead to deposition of IgA immune complexes in the kidney and to nephritis will identified.
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