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Published on: July 27, 2010
Leishmaniavirus-Dependent Metastatic Leishmaniasis Is Prevented by Blocking IL-17A
Mary-Anne Hartley1, Eliane Bourreau2, Matteo Rossi1
1Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
Abstract:
Cutaneous leishmaniasis has various outcomes, ranging from self-healing reddened papules to extensive open ulcerations that metastasise to secondary sites and are often resistant to standard therapies. In the case of L. guyanensis (L.g), about 5-10% of all infections result in metastatic complications. We recently showed that a cytoplasmic virus within L.g parasites (LRV1) is able to act as a potent innate immunogen, worsening disease outcome in a murine model. In this study, we investigated the immunophenotype of human patients infected by L.g and found a significant association between the inflammatory cytokine IL-17A, the presence of LRV1 and disease chronicity. Further, IL-17A was inversely correlated to the protective cytokine IFN-γ. These findings were experimentally corroborated in our murine model, where IL-17A produced in LRV1+ L.g infection contributed to parasite virulence and dissemination in the absence of IFN-γ. Additionally, IL-17A inhibition in mice using digoxin or SR1001, showed therapeutic promise in limiting parasite virulence. Thus, this murine model of LRV1-dependent infectious metastasis validated markers of disease chronicity in humans and elucidated the immunologic mechanism for the dissemination of Leishmania parasites to secondary sites. Moreover, it confirms the prognostic value of LRV1 and IL-17A detection to prevent metastatic leishmaniasis in human patients.
Insights
Leishmania parasites with the LRV1 virus worsen cutaneous leishmaniasis outcomes. Targeting the inflammatory IL-17A cytokine shows therapeutic promise for preventing disease spread.
Area of Science:
- Immunology
- Parasitology
- Infectious Diseases
Background:
- Cutaneous leishmaniasis presents diverse clinical outcomes, from self-healing lesions to metastatic ulcerations resistant to therapy.
- Leishmania guyanensis (L.g) infections can lead to metastatic complications in 5-10% of cases.
- A virus within L.g (LRV1) was previously identified as an innate immunogen exacerbating disease in a murine model.
Purpose of the Study:
- To investigate the immunophenotype of human patients with L.g infection.
- To explore the association between LRV1, IL-17A, and disease chronicity.
- To validate a murine model for studying LRV1-dependent infectious metastasis and therapeutic interventions.
Main Methods:
- Analysis of human patient immunophenotypes.
- Experimental validation in a murine model of L.g infection.
- Assessment of IL-17A inhibition using digoxin and SR1001.
Main Results:
- A significant association was found between IL-17A, LRV1 presence, and disease chronicity in human patients.
- IL-17A was inversely correlated with the protective cytokine IFN-γ.
- In the murine model, IL-17A contributed to parasite virulence and dissemination, while its inhibition showed therapeutic potential.
Conclusions:
- The study identified IL-17A and LRV1 as key players in Leishmania parasite virulence and metastasis.
- The findings validate markers for disease chronicity and provide a mechanism for parasite dissemination.
- LRV1 and IL-17A detection may have prognostic value for preventing metastatic leishmaniasis.
