Journal article

Type I Interferons Suppress Anti-parasitic Immunity and Can Be Targeted to Improve Treatment of Visceral Leishmaniasis

Rajiv Kumar, Patrick T Bunn, Siddharth Sankar Singh, Susanna S Ng, Marcela Montes de Oca, Fabian De labastida Rivera, Shashi Bhushan Chauhan, Neetu Singh, Rebecca J Faleiro, Chelsea L Edwards, Teija CM Frame, Meru Sheel, Rebecca J Austin, Steven W Lane, Tobias Bald, Mark J Smyth, Geoffrey R Hill, Shannon E Best, Ashraful Haque, Dillon Corvino Show all

CELL REPORTS | CELL PRESS | Published : 2020

Abstract

Type I interferons (IFNs) play critical roles in anti-viral and anti-tumor immunity. However, they also suppress protective immune responses in some infectious diseases. Here, we identify type I IFNs as major upstream regulators of CD4+ T cells from visceral leishmaniasis (VL) patients. Furthermore, we report that mice deficient in type I IFN signaling have significantly improved control of Leishmania donovani, a causative agent of human VL, associated with enhanced IFNγ but reduced IL-10 production by parasite-specific CD4+ T cells. Importantly, we identify a small-molecule inhibitor that can be used to block type I IFN signaling during established infection and acts synergistically with co..

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University of Melbourne Researchers

Grants

Awarded by NIH Tropical Medicine Research Centers (TMRC) grant


Awarded by National Health and Medical Research Council of Australia (NHMRC)


Awarded by INSPIRE Faculty fellowship by the Indian government Department of Science and Technology (DST)


Funding Acknowledgements

We thank the staff at the Kala-Azar Medical Research Centre (KAMRC), Muzaffarpur, Bihar, India for help with collecting blood samples as well as patients and volunteers for allowing use of blood samples. We thank the staff at the QIMR Berghofer flow cytometry laboratory for assistance and the staff at the QIMR animal facility for animal husbandry. We thank the NIH tetramer facility (Atlanta, GA) for production of the I-A<SUP>b</SUP>-PEPCK<INF>335-351</INF> tetramer used to detect L. donovani PEPCK-specific CD4<SUP>+</SUP> T cells in these studies. This work was made possible through NIH Tropical Medicine Research Centers (TMRC) grant U19 AI074321 and Queensland State Government funding. The research was supported by grants and fellowships from the National Health and Medical Research Council of Australia (NHMRC; 1037304, 1058685, 1132975, and 1154265) as well as Australian post-graduate awards through Griffith University Institute of Glycomics and School of Natural Sciences (to P.B. and S.S.N., respectively), junior research fellowships from the Indian Council of Medical Research (to S.S.S. and S.B.C.), and an INSPIRE Faculty fellowship (LBSM-109/IF-14 to R.K.) provided by the Indian government Department of Science and Technology (DST).