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Infection and Immunity, December 1999, p. 6249-6256, Vol. 67, No. 12
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Expression of Recombinant Enterotoxigenic Escherichia coli Colonization Factor Antigen I by Salmonella typhimurium Elicits a Biphasic T Helper Cell Response

David W. Pascual,1,* David M. Hone,2 Stacy Hall,3 Frederik W. van Ginkel,3 Masafumi Yamamoto,4 Nancy Walters,1 Kohataro Fujihashi,3 Robert J. Powell,2 Shaoguang Wu,2 John L. Vancott,3 Hiroshi Kiyono,3,4 and Jerry R. McGhee3

Veterinary Molecular Biology, Montana State University, Bozeman, Montana 59717-36101; Institute of Human Virology, University of Maryland Biotechnology Institute, Baltimore, Maryland 212012; Immunobiology Vaccine Center and Departments of Microbiology and Oral Biology, University of Alabama at Birmingham, Birmingham, Alabama 35294-21703; and Department of Mucosal Immunology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565, Japan4

Received 26 July 1999/Accepted 9 September 1999

Protective immunity to enterotoxigenic Escherichia coli (ETEC) is antibody (Ab) dependent; however, oral immunization with purified ETEC fimbriae fails to elicit protective immunity as a consequence of antigenic alteration by the gastrointestinal (GI) tract. Unless unaltered ETEC fimbriae can reach the inductive lymphoid tissues of the GI tract, immunity to ETEC cannot be induced. To produce immunity, live vectors, such as Salmonella typhimurium, can effectively target passenger antigens to the inductive lymphoid tissues of the GI tract. By convention, oral immunizations with Salmonella vectors induce CD4+ T helper (Th) cell responses by gamma interferon (IFN-gamma )-dominated pathways both to the vector and passenger antigen, resulting in serum immunoglobulin G2a (IgG2a) and modest mucosal IgA Ab responses. In the present study, mice orally immunized with a Salmonella vector engineered to stably express ETEC colonization factor antigen I (CFA/I) showed initially elevated serum IgG1 and mucosal IgA anti-CFA/I Ab responses. As expected, mice orally immunized with an E. coli-CFA/I construct elicited poor anti-CFA/I Ab responses. In fact, the addition of cholera toxin during oral E. coli-CFA/I immunization failed to greatly enhance mucosal IgA Ab responses. Seven days after immunization with the Salmonella-CFA/I construct, cytokine-specific ELISPOT showed induction of predominant Th2-type responses in both mucosal and systemic immune compartments supporting the early IgG1 and IgA anti-CFA/I Abs. By 4 weeks, the Th cell response became Th1 cell dominant from the earlier Th2-type responses, as evidenced by increased mucosal and systemic IFN-gamma -producing T cells and a concomitant elevation of serum IgG2a Ab responses. This biphasic response offers an alternative strategy for directing Salmonella vector-induced host immunity along a Th2 cell-dependent pathway, allowing for early promotion of mucosal and systemic Abs.

* Corresponding author. Mailing address: Veterinary Molecular Biology, Montana State University, Bozeman, MT 59717-3610. Phone: (406) 994-6244. Fax: (406) 994-4303. E-mail: dpascual{at}montana.edu.

Infection and Immunity, December 1999, p. 6249-6256, Vol. 67, No. 12
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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Copyright © 1999 by the American Society for Microbiology. All rights reserved.