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

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2020 Feb 27

PMID 32101732

Citations 29

Authors

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 C M Frame

Meru Sheel

Rebecca J Austin

Steven W Lane

Tobias Bald

Mark J Smyth

Geoffrey R Hill

Shannon E Best

Ashraful Haque

Dillon Corvino

Nic Waddell

Lambross Koufariotis

Pamela Mukhopadhay

Madhukar Rai

Jaya Chakravarty

Om Prakash Singh

David Sacks

Susanne Nylen

Jude Uzonna

Shyam Sundar

Christian R Engwerda

Affiliations

Soon will be listed here.

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 conventional anti-parasitic drugs to improve parasite clearance and enhance anti-parasitic CD4 T cell responses in mice and humans. Thus, manipulation of type I IFN signaling is a promising strategy for improving disease outcome in VL patients.

Citing Articles

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

Sepahpour T, Alshaweesh J, Azodi N, Singh K, Ireland D, Valanezhad F NPJ Vaccines. 2024; 9(1):250.

PMID: 39702382 PMC: 11659581. DOI: 10.1038/s41541-024-01032-6.

Kupffer cell and recruited macrophage heterogeneity orchestrate granuloma maturation and hepatic immunity in visceral leishmaniasis.

Pessenda G, Ferreira T, Paun A, Kabat J, Amaral E, Kamenyeva O bioRxiv. 2024; .

PMID: 39372777 PMC: 11451627. DOI: 10.1101/2024.07.09.602717.

A parasite odyssey: An RNA virus concealed in .

Gupta P, Hiller A, Chowdhury J, Lim D, Lim D, Saeij J Virus Evol. 2024; 10(1):veae040.

PMID: 38817668 PMC: 11137675. DOI: 10.1093/ve/veae040.

Innate biosignature of treatment failure in human cutaneous leishmaniasis.

Gomez M, Belew A, Vargas D, Giraldo-Parra L, Rebellon-Sanchez D, Alexander T Res Sq. 2024; .

PMID: 38746226 PMC: 11092798. DOI: 10.21203/rs.3.rs-4271873/v1.

Silver and gold nanoparticles as a novel approach to fight Sarcoptic mange in rabbits.

Hassanen E, Morsy E, Abuowarda M, Ibrahim M, Shaalan M Sci Rep. 2024; 14(1):10618.

PMID: 38724594 PMC: 11081955. DOI: 10.1038/s41598-024-60736-w.

References

Xing L, Dai Z, Jabbari A, Cerise J, Higgins C, Gong W . Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition. Nat Med. 2014; 20(9):1043-9. PMC: 4362521. DOI: 10.1038/nm.3645. View

Sundar S, Singh A, Singh O . Strategies to overcome antileishmanial drugs unresponsiveness. J Trop Med. 2014; 2014:646932. PMC: 4021741. DOI: 10.1155/2014/646932. View

Engwerda C, Kaye P . Organ-specific immune responses associated with infectious disease. Immunol Today. 2000; 21(2):73-8. DOI: 10.1016/s0167-5699(99)01549-2. View

Moreira-Teixeira L, Redford P, Stavropoulos E, Ghilardi N, Maynard C, Weaver C . T Cell-Derived IL-10 Impairs Host Resistance to Infection. J Immunol. 2017; 199(2):613-623. PMC: 5502318. DOI: 10.4049/jimmunol.1601340. View

Rossi M, Castiglioni P, Hartley M, Eren R, Prevel F, Desponds C . Type I interferons induced by endogenous or exogenous viral infections promote metastasis and relapse of leishmaniasis. Proc Natl Acad Sci U S A. 2017; 114(19):4987-4992. PMC: 5441690. DOI: 10.1073/pnas.1621447114. View

Haque A, Best S, Montes de Oca M, James K, Ammerdorffer A, Edwards C . Type I IFN signaling in CD8- DCs impairs Th1-dependent malaria immunity. J Clin Invest. 2014; 124(6):2483-96. PMC: 4038565. DOI: 10.1172/JCI70698. View

Kumar R, Bhushan Chauhan S, Ng S, Sundar S, Engwerda C . Immune Checkpoint Targets for Host-Directed Therapy to Prevent and Treat Leishmaniasis. Front Immunol. 2017; 8:1492. PMC: 5682306. DOI: 10.3389/fimmu.2017.01492. View

Hopman R, Lawrence S, Oh S . Disseminated tuberculosis associated with ruxolitinib. Leukemia. 2014; 28(8):1750-1. DOI: 10.1038/leu.2014.104. View

Sheehan K, Lai K, Dunn G, Bruce A, Diamond M, Heutel J . Blocking monoclonal antibodies specific for mouse IFN-alpha/beta receptor subunit 1 (IFNAR-1) from mice immunized by in vivo hydrodynamic transfection. J Interferon Cytokine Res. 2006; 26(11):804-19. DOI: 10.1089/jir.2006.26.804. View

10.

Engwerda C, Ng S, Bunn P . The Regulation of CD4(+) T Cell Responses during Protozoan Infections. Front Immunol. 2014; 5:498. PMC: 4195384. DOI: 10.3389/fimmu.2014.00498. View

11.

Bhagwat N, Koppikar P, Keller M, Marubayashi S, Shank K, Rampal R . Improved targeting of JAK2 leads to increased therapeutic efficacy in myeloproliferative neoplasms. Blood. 2014; 123(13):2075-83. PMC: 3968390. DOI: 10.1182/blood-2014-01-547760. View

12.

Tumang M, Keogh C, Moldawer L, Helfgott D, Teitelbaum R, Hariprashad J . Role and effect of TNF-alpha in experimental visceral leishmaniasis. J Immunol. 1994; 153(2):768-75. View

13.

Ladislau L, Suarez-Calvet X, Toquet S, Landon-Cardinal O, Amelin D, Depp M . JAK inhibitor improves type I interferon induced damage: proof of concept in dermatomyositis. Brain. 2018; 141(6):1609-1621. DOI: 10.1093/brain/awy105. View

14.

DeLuca D, Levin J, Sivachenko A, Fennell T, Nazaire M, Williams C . RNA-SeQC: RNA-seq metrics for quality control and process optimization. Bioinformatics. 2012; 28(11):1530-2. PMC: 3356847. DOI: 10.1093/bioinformatics/bts196. View

15.

Harrison C, Kiladjian J, Al-Ali H, Gisslinger H, Waltzman R, Stalbovskaya V . JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012; 366(9):787-98. DOI: 10.1056/NEJMoa1110556. View

16.

Bradley D, KIRKLEY J . Regulation of Leishmania populations within the host. I. the variable course of Leishmania donovani infections in mice. Clin Exp Immunol. 1977; 30(1):119-29. PMC: 1541173. View

17.

Kaye P, Svensson M, Ato M, Maroof A, Polley R, Stager S . The immunopathology of experimental visceral leishmaniasis. Immunol Rev. 2004; 201:239-53. DOI: 10.1111/j.0105-2896.2004.00188.x. View

18.

Singh O, Sundar S . Immunotherapy and targeted therapies in treatment of visceral leishmaniasis: current status and future prospects. Front Immunol. 2014; 5:296. PMC: 4135235. DOI: 10.3389/fimmu.2014.00296. View

19.

Bunn P, Montes de Oca M, De Labastida Rivera F, Kumar R, Ng S, Edwards C . Distinct Roles for CD4 Foxp3 Regulatory T Cells and IL-10-Mediated Immunoregulatory Mechanisms during Experimental Visceral Leishmaniasis Caused by . J Immunol. 2018; 201(11):3362-3372. DOI: 10.4049/jimmunol.1701582. View

20.

Butler N, Moebius J, Pewe L, Traore B, Doumbo O, Tygrett L . Therapeutic blockade of PD-L1 and LAG-3 rapidly clears established blood-stage Plasmodium infection. Nat Immunol. 2011; 13(2):188-95. PMC: 3262959. DOI: 10.1038/ni.2180. View