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A High Resolution Method to Monitor Phosphorylation-dependent Activation of IRF3
Published on: January 24, 2016
Downregulation of IRF7-mediated type-I interferon response by LmCen-/- parasites is necessary for protective immunity
Telly Sepahpour1, Jalal Alshaweesh2, Nazli Azodi1
1Division of Emerging and Transfusion Transmitted Diseases, CBER, FDA, Silver Spring, MD, 20993, USA.
Abstract:
Leishmaniasis is a tropical disease caused by Leishmania parasites and currently has no licensed vaccines. We developed a dermotropic Leishmania major centrin gene-deleted strain (LmCen-/-) as a live attenuated vaccine. Recent studies have shown that type I interferons (IFNs) play important roles in immunity to parasitic and viral pathogens. However, their relevance in protective immunity following vaccination is not understood. We found that immunization with LmCen-/- induces a transient increase in type I IFN response along with its regulatory factor IRF7 that is downregulated 7-21 days post-immunization, coincided with the induction of a robust Th1 adaptive immune response. Challenge infection with virulent L. donovani parasites showed a significant reduction of splenic and hepatic parasite burden in IRF7-/- mice than wild type mice following immunization with LmCen-/-, suggesting that ablation of type I IFN response is a pre-requisite for the induction of LmCen-/- mediated Th1 immunity against L. donovani infection.
Insights
A new live attenuated vaccine for leishmaniasis shows promise. Ablating the type I interferon response is crucial for the vaccine to induce protective immunity against Leishmania donovani infection.
Area of Science:
- Immunology
- Tropical Diseases
- Vaccinology
Background:
- Leishmaniasis is a neglected tropical disease with no approved vaccines.
- Type I interferons (IFNs) are critical for pathogen defense, but their role in vaccine-induced immunity is unclear.
Purpose of the Study:
- To investigate the role of type I IFNs in the protective immunity induced by a novel live attenuated Leishmania major vaccine (LmCen-/-).
Main Methods:
- Immunization of mice with LmCen-/- vaccine.
- Analysis of type I IFN response and IRF7 expression post-immunization.
- Challenge infection with virulent Leishmania donovani parasites in wild-type and IRF7-/- mice.
Main Results:
- LmCen-/- immunization transiently increased type I IFN and IRF7, followed by downregulation.
- This downregulation coincided with the development of a strong Th1 immune response.
- IRF7-/- mice showed reduced parasite burden after vaccination and challenge compared to wild-type mice.
Conclusions:
- Ablation of the type I interferon response is essential for the LmCen-/- vaccine to induce protective Th1 immunity against Leishmania donovani.
- This finding has implications for designing effective leishmaniasis vaccines.
