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Infection and Immunity, September 2000, p. 4930-4937, Vol. 68, No. 9
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Phagocytic Cell Killing Mediated by Secreted Cytotoxic Factors of Vibrio cholerae

Vasu Punj,1 Olga Zaborina,1 Neelam Dhiman,1 Kim Falzari,1 M. Bagdasarian,2 and A. M. Chakrabarty1,*

Department of Microbiology & Immunology, University of Illinois College of Medicine, Chicago, Illinois 60612,1 and Department of Microbiology, Michigan State University, East Lansing, Michigan 488242

Received 31 March 2000/Returned for modification 16 May 2000/Accepted 31 May 2000

Vibrio cholerae strain VB1 secretes a number of enzymes into the outside medium that utilize ATP as a substrate. Such enzymes are found in the outside medium during the mid-log phase of growth, when the optical density at 650 nm is about 0.4, and they demonstrate nucleoside diphosphate kinase (Ndk), 5' nucleotidase, and adenylate kinase (Ak) activities. We report that the filtered growth medium of V. cholerae, as well as the flowthrough fraction of a green Sepharose column during fractionation of the growth medium, had very little cytotoxicity by itself towards macrophages and mast cells but exhibited significant cytotoxicity in the presence of exogenous ATP. Such fractions, harboring 5' nucleotidase, Ndk, and presumably other ATP-utilizing enzymes, demonstrated enhanced macrophage and mast cell death; periodate-oxidized-ATP (oATP)-treated macrophage and mast cells or such cells exposed to 0.1 mM Mg2+, where surface-associated P2Z receptors could not be activated, were not susceptible to subsequent ATP addition. Microscopic visualization of mast cells clearly demonstrated cell morphological changes such as swelling, vacuolization, and nuclear fragmentation following treatment with ATP and the growth medium of V. cholerae; however, these effects were suppressed if the mast cells were pretreated with oATP. These results strongly imply that the secreted ATP-utilizing enzymes of V. cholerae modulate the external ATP levels of the macrophage and mast cells, leading to their accelerated death, presumably through activation of P2Z receptors. Thus, development of inhibitors for such enzymes may reduce the level of V. cholerae infection; alternatively, mutations in such genes may eliminate V. cholerae survival in the gut and contribute to a safer live vaccine.

* Corresponding author. Mailing address: A. M. Chakrabarty, Department of Microbiology & Immunology, M/C 790, University of Illinois College of Medicine, 835 South Wolcott Ave., Chicago, IL 60612. Phone: (312) 996-4586. Fax: (312) 996-6415. E-mail: Ananda.Chakrabarty{at}uic.edu.

Infection and Immunity, September 2000, p. 4930-4937, Vol. 68, No. 9
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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