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Infection and Immunity, November 2006, p. 6027-6036, Vol. 74, No. 11
0019-9567/06/$08.00+0     doi:10.1128/IAI.00773-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Spontaneous Recovery of Pathogenicity by Leishmania major hsp100–/– Alters the Immune Response in Mice

Linda Reiling ,1,{dagger},{ddagger} Thomas Jacobs,2,{ddagger} Manfred Kroemer,1 Iris Gaworski,2 Sebastian Graefe,2 and Joachim Clos1*

Leishmaniasis Unit 1,1 Department of Medical Microbiology and Immunology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany2

Received 23 May 2005/ Returned for modification 1 August 2005/ Accepted 6 August 2006

By using repeated mouse infection cycles, we obtained an escape variant with restored infectivity and pathogenicity that originated from a single, noninfectious hsp100–/– gene (formerly known as {Delta}clpB) replacement clone of Leishmania major, the causative agent of cutaneous leishmaniasis. This isolate elicited increased infiltration of immune cells to the site of infection and altered the polarization of the immune response in BALB/c mice from a predominantly TH2 type to a TH1 type. A clonal analysis resulted in isolation of two clones with antagonistic properties. While one clone exhibited restored infectivity in isolated macrophages but caused no persistent infection in the mouse model, the second clone was unable to infect macrophages in vitro but could establish a lasting infection and form progressive lesions in BALB/c mice. Our results add to the evidence that the TH1-TH2 dichotomy of the early immune response against L. major not only depends on the genetic predisposition of the host but also depends on intrinsic properties of the parasite.

* Corresponding author. Mailing address: Bernhard Nocht Institute for Tropical Medicine, Bernhard Nocht St. 74, D-20359 Hamburg, Germany. Phone: 49-40-42818 481. Fax: 49-40-42818 512. E-mail: clos{at}bni-hamburg.de.

Editor: J. F. Urban, Jr.

{dagger} Present address: The Walter and Eliza Hall Institute, Infection and Immunity Division, 1G Royal Parade, Parkville, Victoria 3050, Australia.

{ddagger} L.R. and T.J. contributed equally to this paper.

Infection and Immunity, November 2006, p. 6027-6036, Vol. 74, No. 11
0019-9567/06/$08.00+0     doi:10.1128/IAI.00773-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.





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