Downregulation of IRF7-mediated type-I interferon response by LmCen-/- parasites is necessary for protective immunity

Telly Sepahpour; Jalal Alshaweesh; Nazli Azodi; Komudi Singh; Derek D C Ireland; Farzaneh Valanezhad; Risa Nakamura; Abhay R Satoskar; Ranadhir Dey; Shinjiro Hamano; Hira L Nakhasi; Sreenivas Gannavaram

doi:10.1038/s41541-024-01032-6

Downregulation of IRF7-mediated type-I interferon response by LmCen^-/- parasites is necessary for protective immunity

NPJ Vaccines. 2024 Dec 19;9(1):250. doi: 10.1038/s41541-024-01032-6.

Authors

Affiliations

¹ Division of Emerging and Transfusion Transmitted Diseases, CBER, FDA, Silver Spring, MD, 20993, USA.
² Department of Parasitology, Institute of Tropical Medicine (NEKKEN), The Joint Usage/Research Center on Tropical Disease, Nagasaki University, Nagasaki, Japan, and Graduate School of Biomedical Sciences, Doctoral Leadership Program, Nagasaki University, Nagasaki, Japan.
³ National Heart Lung Blood Institute (NHLBI), NIH, Bethesda, MD, USA.
⁴ Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.
⁵ Department of Pathology and Microbiology, Ohio State University, Columbus, OH, USA.
⁶ Division of Emerging and Transfusion Transmitted Diseases, CBER, FDA, Silver Spring, MD, 20993, USA. [email protected].
⁷ Department of Parasitology, Institute of Tropical Medicine (NEKKEN), The Joint Usage/Research Center on Tropical Disease, Nagasaki University, Nagasaki, Japan, and Graduate School of Biomedical Sciences, Doctoral Leadership Program, Nagasaki University, Nagasaki, Japan. [email protected].
⁸ Division of Emerging and Transfusion Transmitted Diseases, CBER, FDA, Silver Spring, MD, 20993, USA. [email protected].
⁹ Division of Emerging and Transfusion Transmitted Diseases, CBER, FDA, Silver Spring, MD, 20993, USA. [email protected].

^# Contributed equally.

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.