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Infection and Immunity, December 2000, p. 6602-6610, Vol. 68, No. 12
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Dual Role of Signaling Pathways Leading to Ca2+ and Cyclic AMP Elevation in Host Cell Invasion by Trypanosoma cruzi

Elisabet V. Caler,1 Rory E. Morty,1 Barbara A. Burleigh,2 and Norma W. Andrews1,*

Section of Microbial Pathogenesis, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, Connecticut 06520,1 and the Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts 021552

Received 6 July 2000/Returned for modification 19 August 2000/Accepted 4 September 2000

Cell invasion by the protozoan parasite Trypanosoma cruzi involves activation of host signaling pathways and the recruitment and fusion of lysosomes at the parasite entry site. A major signaling pathway regulating invasion of fibroblasts, epithelial cells, and myoblasts involves mobilization of Ca2+ from intracellular stores and requires the activity of a T. cruzi serine peptidase, oligopeptidase B (OPB). Deletion of the OPB gene results in a marked defect in trypomastigote virulence, consistent with a greatly reduced cell invasion capacity. Here we show that uptake by macrophages, on the other hand, is largely independent of OPB expression and sensitive to inhibition of by cytochalasin D. The residual invasion capacity of OPBnull trypomastigotes in fibroblasts still involves lysosome recruitment, although in a significantly delayed fashion. Transient elevations in intracellular Ca2+ concentrations were observed in host cells exposed to both wild-type and OPBnull trypomastigotes, but the signals triggered by the mutant parasites were less vigorous and delayed. The capacity of triggering elevation in host cell cyclic AMP (cAMP), however, was unaltered in OPBnull trypomastigotes. Modulation in cAMP levels preferentially affected the residual cell invasion capacity of OPBnull parasites, suggesting that this signaling pathway can play a dominant role in promoting cell invasion in the absence of the major OPB-dependent pathway.

* Corresponding author. Mailing address: Section of Microbial Pathogenesis, Boyer Center for Molecular Medicine, Yale University School of Medicine, 295 Congress Ave., New Haven, CT 06536. Phone: (203) 737-2410. Fax: (203) 737-2630. E-mail: norma.andrews{at}yale.edu.

Infection and Immunity, December 2000, p. 6602-6610, Vol. 68, No. 12
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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