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

• Published in: Infection and Immunity 2006-11, Vol.74 (11), p.6027-6036
• Main Authors: Reiling, Linda, Jacobs, Thomas, Kroemer, Manfred, Gaworski, Iris, Graefe, Sebastian, Clos, Joachim
• Format: Article
• Language: English
• Subjects: Animals; Cell Movement - immunology; Cells, Cultured; Disease Models, Animal; Endopeptidase Clp; Female; Heat-Shock Proteins - deficiency; Heat-Shock Proteins - genetics; Heat-Shock Proteins - physiology; Leishmania major - genetics; Leishmania major - growth & development; Leishmania major - immunology; Leishmania major - pathogenicity; Leishmaniasis, Cutaneous - immunology; Leishmaniasis, Cutaneous - parasitology; Leishmaniasis, Cutaneous - pathology; Macrophages, Peritoneal - immunology; Macrophages, Peritoneal - metabolism; Macrophages, Peritoneal - parasitology; Mice; Mice, Inbred BALB C; Molecular Pathogenesis; Protozoan Proteins - genetics; Protozoan Proteins - physiology; Th1 Cells - immunology; Th1 Cells - metabolism; Th1 Cells - microbiology; Th2 Cells - immunology; Th2 Cells - metabolism; Th2 Cells - microbiology
• ISSN: 0019-9567; 1098-5522
• DOI: 10.1128/IAI.00773-05

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 ΔclpB) 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.