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

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Type I Interferons Suppress Anti-parasitic Immunity and Can Be Targeted to Improve Treatment of Visceral Leishmaniasis.
Cell Reports ( IF 7.5 ) Pub Date : 2020-02-25 , DOI: 10.1016/j.celrep.2020.01.099
Rajiv Kumar ₁ , Patrick T Bunn ₂ , Siddharth Sankar Singh ₃ , Susanna S Ng ₄ , Marcela Montes de Oca ₅ , Fabian De Labastida Rivera ₅ , Shashi Bhushan Chauhan ₃ , Neetu Singh ₃ , Rebecca J Faleiro ₅ , Chelsea L Edwards ₆ , Teija C M Frame ₅ , Meru Sheel ₇ , Rebecca J Austin ₅ , Steven W Lane ₅ , Tobias Bald ₅ , Mark J Smyth ₅ , Geoffrey R Hill ₈ , Shannon E Best ₅ , Ashraful Haque ₅ , Dillon Corvino ₅ , Nic Waddell ₅ , Lambross Koufariotis ₅ , Pamela Mukhopadhay ₅ , Madhukar Rai ₃ , Jaya Chakravarty ₃ , Om Prakash Singh ₃ , David Sacks ₉ , Susanne Nylen ₁₀ , Jude Uzonna ₁₁ , Shyam Sundar ₃ , Christian R Engwerda ₅

Affiliation

Centre of Experimental Medicine and Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi, UP, India; Department of Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, UP, India.
QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; Griffith University, Institute of Glycomics, Gold Coast, QLD, Australia.
Department of Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, UP, India.
QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; Griffith University, School of Natural Sciences, Nathan, QLD, Australia.
QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; University of Queensland, School of Medicine, Brisbane, QLD Australia.
QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; National Centre for Epidemiology and Population Health, Research School of Population Health, College of Health and Medicine, The Australian National University, Canberra, ACT, Australia.
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA.
Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden.
Department of Immunology, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada.

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.

中文翻译：

I 型干扰素抑制抗寄生虫免疫，可靶向改善内脏利什曼病的治疗。

I 型干扰素 (IFN) 在抗病毒和抗肿瘤免疫中起关键作用。然而，它们也会抑制某些传染病的保护性免疫反应。在这里，我们将 I 型 IFN 确定为来自内脏利什曼病 (VL) 患者的 CD4+ T 细胞的主要上游调节剂。此外，我们报告说，I 型 IFN 信号传导缺陷的小鼠显着改善了对杜氏利什曼原虫（一种人类 VL 的病原体）的控制，与增强的 IFNγ 相关，但减少了寄生虫特异性 CD4+ T 细胞产生的 IL-10。重要的是，我们确定了一种小分子抑制剂，可用于在感染期间阻断 I 型 IFN 信号传导，并与常规抗寄生虫药物协同作用，以改善寄生虫清除并增强小鼠和人类的抗寄生虫 CD4+ T 细胞反应。因此，

更新日期：2020-02-25

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