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Spontaneous recovery of pathogenicity by Leishmania major hsp100-/- alters the immune response in mice
Linda Reiling1, Thomas Jacobs, Manfred Kroemer
1Leishmaniasis Unit 1, Department of Medical Microbiology and Immunology, Bernhard Nocht Institute for Tropical Medicine, Bernhard Nocht St. 74, D-20359 Hamburg, Germany.
Abstract:
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 DeltaclpB) 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.
Insights
Researchers developed a Leishmania major variant that causes more severe disease by altering immune responses. This study highlights how parasite properties, not just host genetics, influence Leishmania infection outcomes.
Area of Science:
- Parasitology
- Immunology
- Molecular Biology
Background:
- Leishmania major causes cutaneous leishmaniasis.
- The immune response to L. major involves a TH1-TH2 dichotomy.
- Parasite factors can influence disease progression.
Purpose of the Study:
- To generate and characterize an escape variant of L. major with restored pathogenicity.
- To investigate the impact of parasite variants on host immune responses.
- To understand the interplay between parasite intrinsic properties and host genetics in leishmaniasis.
Main Methods:
- Repeated mouse infection cycles to select for escape variants.
- Gene replacement using hsp100-/-.
- Immune cell infiltration analysis.
- Immune response polarization assessment (TH1/TH2).
- Clonal analysis of parasite variants.
Main Results:
- An hsp100-/- replacement clone of L. major regained infectivity and pathogenicity.
- The escape variant induced increased immune cell infiltration and shifted BALB/c mice from TH2 to TH1 response.
- Two antagonistic clones were isolated: one infects macrophages but not mice, the other infects mice but not macrophages in vitro.
- The second clone established lasting infections and progressive lesions in mice.
Conclusions:
- The TH1-TH2 immune response balance in L. major infections depends on both host genetic predisposition and parasite intrinsic properties.
- Parasite escape variants can significantly alter disease course and immune polarization.
- Understanding parasite virulence factors is crucial for developing effective leishmaniasis treatments.
