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Infection and Immunity, May 2000, p. 2728-2734, Vol. 68, No. 5
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Heterologous Expression of Trypanosoma cruzi trans-Sialidase in Leishmania major Enhances Virulence

M. Belen Carrillo,1,dagger Wenda Gao,1 Macario Herrera,1 Joseph Alroy,2 Jeffrey B. Moore,3,Dagger Stephen M. Beverley,4 and Miercio A. Pereira1,*

Parasitology Research Center, Department of Pathology, Tufts University School of Medicine,1 and Department of Pathology, Tufts University School of Veterinary Medicine, and New England Medical Center,2 Boston, Massachusetts 02111; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 021153; and Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 631104

Received 29 November 1999/Returned for modification 11 January 2000/Accepted 4 February 2000

Earlier studies showed that mice primed for a few hours with the trans-sialidase (TS) of Trypanosoma cruzi, the agent of Chagas' disease, become highly susceptible to trypanosomal infection. These studies suggest that TS affects parasite virulence independent of antigenic stimulation. Potentially, TS could enhance or reduce the virulence of heterologous microbes depending on the mechanism of TS action and on the type of immune response elicited by the particular parasite. We tested this hypothesis by expressing heterologous TS in Leishmania major, a protozoan parasite that causes cutaneous leishmaniasis and lacks TS and the TS product alpha 2-3-linked sialic acid. Leishmania cells transfected with a T. cruzi TS expression construct made high levels of active enzyme, which was present in the promastigotes and shed into the extracellular milieu. TS expression did not affect L. major binding to and entry into cultured macrophages or its tropism for macrophage infection in vivo. However, TS-expressing L. major exhibited elevated virulence in BALB/c mice, as determined by lesion progression, parasite numbers, and macro- and microscopic examination of cutaneous lesions. Several genetic tests proved that the enhanced virulence was directly attributable to TS expression. The results are consistent with TS functioning to sabotage the mouse immune system to confer a growth advantage on T. cruzi and transgenic L. major. These data suggest that heterologous expression of T. cruzi virulence factors in Leishmania may provide a new approach for dissecting their function in vivo.

* Corresponding author. Mailing address: Department of Pathology, Parasitology Research Center, Tufts Medical School, 136 Harrison Avenue, Boston, MA 02111. Phone: 617-636-2933. Fax: 617-636-6849. E-mail: maperrin{at}yahoo.com.

dagger Present address: The Center for Blood Research, Department of Pathology, Harvard Medical School, Boston, MA 02115.

Dagger Present address: Millennium Pharmaceuticals, Inc., Cambridge, MA 02139.

Infection and Immunity, May 2000, p. 2728-2734, Vol. 68, No. 5
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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