Browsing by Author "Siddharth Sankar Singh"

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A molecular signature for CD8+ T cells from visceral leishmaniasis patients
(Blackwell Publishing Ltd, 2019) Bhawana Singh; Shashi Bhushan Chauhan; Rajiv Kumar; Siddharth Sankar Singh; Susanna Ng; Fiona Amante; Fabian de Labastida Rivera; Om Prakash Singh; Madhukar Rai; Susanne Nylen; Shyam Sundar; Christian Engwerda
CD8+ T-cell function is compromised in chronic diseases such as visceral leishmaniasis (VL). However, little is known about the changes in gene expression that cause CD8+ T-cell dysfunction during VL. We used targeted transcriptional profiling of peripheral blood CD8+ T cells from VL patients pre- and post-anti-parasitic drug treatment, and compared them with the same cell population from healthy endemic controls to assess their activation, differentiation and functional status during disease. We found a predominance of downregulated immune genes in CD8+ T cells from VL patients. However, genes encoding several notable immune checkpoint molecules, including LAG-3, TIM-3 and CTLA-4, cytolytic molecules, such as granzymes A, B and H and perforin, as well as SOCS3, STAT1, JAK2 and JAK3 cytokine signalling genes were found to be increasingly expressed by VL patient CD8+ T cells. Additional studies confirmed increased expression of the inhibitory receptors LAG3 and TIM3 on VL patient CD8+ T cells, thereby identifying these molecules as potential targets to improve antigen-specific CD8+ T-cell responses during disease. © 2019 John Wiley & Sons Ltd
A molecular signature for IL-10–producing Th1 cells in protozoan parasitic diseases
(American Society for Clinical Investigation, 2023) Chelsea L. Edwards; Jessica A. Engel; Fabian de Labastida Rivera; Susanna S. Ng; Dillon Corvino; Marcela Montes de Oca; Teija C.M. Frame; Shashi Bhushan Chauhan; Siddharth Sankar Singh; Awnish Kumar; Yulin Wang; Jinrui Na; Pam Mukhopadhyay; Jason S. Lee; Susanne Nylen; Shyam Sundar; Rajiv Kumar; Christian R. Engwerda
Control of visceral leishmaniasis (VL) depends on proinflammatory Th1 cells that activate infected tissue macrophages to kill resident intracellular parasites. However, proinflammatory cytokines produced by Th1 cells can damage tissues and require tight regulation. Th1 cell IL-10 production is an important cell–autologous mechanism to prevent such damage. However, IL-10–producing Th1 (type 1 regulatory; Tr1) cells can also delay control of parasites and the generation of immunity following drug treatment or vaccination. To identify molecules to target in order to alter the balance between Th1 and Tr1 cells for improved antiparasitic immunity, we compared the molecular and phenotypic profiles of Th1 and Tr1 cells in experimental VL caused by Leishmania donovani infection of C57BL/6J mice. We also identified a shared Tr1 cell protozoan signature by comparing the transcriptional profiles of Tr1 cells from mice with experimental VL and malaria. We identified LAG3 as an important coinhibitory receptor in patients with VL and experimental VL, and we reveal tissue-specific heterogeneity of coinhibitory receptor expression by Tr1 cells. We also discovered a role for the transcription factor Pbx1 in suppressing CD4+ T cell cytokine production. This work provides insights into the development and function of CD4+ T cells during protozoan parasitic infections and identifies key immunoregulatory molecules. © 2023, Edwards et al.
Abnormal b-cell subset and blimp-1-mediated humoral responses associated with visceral leishmaniasis pathogenesis
(American Society of Tropical Medicine and Hygiene, 2019) Bhawana Singh; Om Prakash Singh; Neetu Singh; Siddharth Sankar Singh; Shyam Sundar
B-cells have a spectrum of functions ranging from antibody production to antigen presentation and have additional vital roles in immune mechanisms. There is rudimentary knowledge about the role of B-cells in intracellular infections with contradictory findings. We explored the role of B-cell dysfunctions in visceral leishmaniasis (VL) pathogenesis in terms of the phenotypic and functional properties of B-cells during the course of disease. This study was performed on blood and splenic aspirates (SA) of VL cases pre- and post-treatment. Whole blood was used for flow cytometric studies for determining the profiles of B-cells at different time-points of treatment. Peripheral blood mononuclear cells were used for magnetic purification of B-cells, for transcriptional studies by real-time polymerase chain reaction (RT-PCR). Serum/plasma was used for direct agglutination test for determining parasite-specific antibodies and SAwere usedfor scoringthepresence ofparasitebymicroscopic examination. Flowcytometric studiesdepicteddecreased B-cell percentages during the entire course of disease and attainment of exhaustive phenotypewith tissue-likememory cell markers, indicative of B-cell dysfunctions in VL. In addition, B-cells had compromised abilities of antigen processing and presentation and altered levels of B-lymphocyte-induced maturation protein-1 (Blimp-1). Blimp-1 expression goes hand in hand with B-cell maturation antigen and transmembrane activator and calcium modulator (TACI) and cyclophilin ligand interactor, suggestive of its role in promoting plasma cell survival and antibody production. Elevated level of VL-specific antibody titre was directly correlated with exhausted phenotype and also with disease severity during VL. This study indicated for impaired B-cell functions during chronic infection which may lead to pathological consequences in human VL. © 2019 by The American Society of Tropical Medicine and Hygiene.
Altered IL-7 signaling in CD4+ T cells from patients with visceral leishmaniasis
(Public Library of Science, 2024) Shashi Kumar; Shashi Bhushan Chauhan; Shreya Upadhyay; Siddharth Sankar Singh; Vimal Verma; Rajiv Kumar; Christian Engwerda; Susanne Nylén; Shyam Sundar
Background CD4+ T cells play a central role in control of L. donovani infection, through IFN-γ production required for activation of macrophages and killing of intracellular parasites. Impaired control of parasites can in part be explained by hampered CD4+ T cells effector functions in visceral leishmaniasis (VL) patients. In a recent studies that defined transcriptional signatures for CD4+ T cells from active VL patients, we found that expression of the IL-7 receptor alpha chain (IL-7RΑ; CD127) was downregulated, compared to CD4+ T cells from endemic controls (ECs). Since IL-7 signaling is critical for the survival and homeostatic maintenance of CD4+ T cells, we investigated this signaling pathway in VL patients, relative to ECs. Methods CD4+ T cells were enriched from peripheral blood collected from VL patients and EC subjects and expression of IL7 and IL7RA mRNA was measured by real time qPCR. IL-7 signaling potential and surface expression of CD127 and CD132 on CD4+ T cell was analyzed by multicolor flow cytometry. Plasma levels of soluble IL-7 and sIL-7Rα were measured by ELISA. Result Transcriptional profiling data sets generated previously from our group showed lower IL7RA mRNA expression in VL CD4+ T cells as compared to EC. A significant reduction was, however not seen when assessing IL7RA mRNA by RT-qPCR. Yet, the levels of soluble IL-7Rα (sIL-7Rα) were reduced in plasma of VL patients compared to ECs. Furthermore, the levels of soluble IL-7 were higher in plasma from VL patients compared to ECs. Interestingly, expression of the IL-7Rα protein was higher on VL patient CD4+ T cells as compared to EC, with activated CD38+ CD4+ T cells showing higher surface expression of IL-7Rα compared to CD38- CD4+ T cells in VL patients. CD4+ T cells from VL patients had higher signaling potential baseline and after stimulation with recombinant human IL-7 (rhIL-7) compared to EC, as measured by phosphorylation of STAT5 (pSTAT5). Interestingly, it was the CD38 negative cells that had the highest level of pSTAT5 in VL patient CD4+ T cells after IL-7 stimulation. Thus, despite unaltered or potentially lowered IL7RA mRNA expression by CD4+ T cells from VL patients, the surface expression of the IL-7Rα was higher compared to EC and increased pSTAT5 was seen following exposure to rhIL-7. Accordingly, IL-7 signaling appears to be functional and even enhanced in VL CD4+ T cells and cannot explain the impaired effector function of VL CD4+ T cells. The enhanced plasma IL-7 may serve as part of homeostatic feedback mechanism regulating IL7RA expression in CD4+ T cells. © 2024 Kumar et al.
Correction to: The NK cell granule protein NKG7 regulates cytotoxic granule exocytosis and inflammation (Nature Immunology, (2020), 21, 10, (1205-1218), 10.1038/s41590-020-0758-6)
(Nature Research, 2024) Susanna S. Ng; Fabian De Labastida Rivera; Juming Yan; Dillon Corvino; Indrajit Das; Ping Zhang; Rachel Kuns; Shashi Bhushan Chauhan; Jiajie Hou; Xian-Yang Li; Teija C. M. Frame; Benjamin A. McEnroe; Eilish Moore; Jinrui Na; Jessica A. Engel; Megan S. F. Soon; Bhawana Singh; Andrew J. Kueh; Marco J. Herold; Marcela Montes de Oca; Siddharth Sankar Singh; Patrick T. Bunn; Amy Roman Aguilera; Mika Casey; Matthias Braun; Nazanin Ghazanfari; Shivangi Wani; Yulin Wang; Fiona H. Amante; Chelsea L. Edwards; Ashraful Haque; William C. Dougall; Om Prakash Singh; Alan G. Baxter; Michele W. L. Teng; Alex Loukas; Norelle L. Daly; Nicole Cloonan; Mariapia A. Degli-Esposti; Jude Uzonna; William R. Heath; Tobias Bald; Siok-Keen Tey; Kyohei Nakamura; Geoffrey R. Hill; Rajiv Kumar; Shyam Sundar; Mark J. Smyth; Christian R. Engwerda
Correction to: Nature Immunologyhttps://doi.org/10.1038/s41590-020-0758-6, published online 24 August 2020. The Chief Editor is correcting this article at the request of the corresponding author, Christian Engwerda. An investigation by QIMR Berghofer Medical Research Institute found that the original Figs. 7e, 7h (upper panel) and 8a and Extended Data Fig. 5b (EO771 data only) were based on experiments for which no evidence of their conduct or primary data could be confirmed. As such, the data from the underlying experiments are believed to have been fabricated or are unreliable, respectively. The four panels have been removed from Figs. 7 and 8 and Extended Data Fig. 5 (see Supplementary Information for a list of edits and original article for comparison). The major finding of the paper that NKG7 regulates cytotoxic granule exocytosis and inflammation remains unaffected. No concerns have been raised regarding other data in the paper. © The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.
Emerging role of γδ T cells in protozoan infection and their potential clinical application
(Elsevier B.V., 2022) Awnish Kumar; Bhawana Singh; Rahul Tiwari; Vishal Kumar Singh; Siddharth Sankar Singh; Shyam Sundar; Rajiv Kumar
γδ T cells are thymus derived heterogeneous and unconventional T- lymphocyte expressing TCR γ (V γ9) and TCRδ (Vδ2) chain and play an important role in connecting innate and adaptive armaments of immune response. These cells can recognize wide ranges of antigens even without involvement of major histocompatibility complex and exert their biological functions by cytotoxicity or activating various types of immune cells. In recent past, γδ T cells have emerged as an important player during protozoa infection and rapidly expand after exposure with them. They have also been widely studied in vaccine induced immune response against many bacterial and protozoan infections with improved clinical outcome. In this review, we will discuss the various roles of γδ T cells in immunity against malaria and leishmaniasis, the two important protozoan diseases causing significant mortality and morbidity throughout the world. © 2022
Hepcidin mediated iron homoeostasis as immune regulator in visceral leishmaniasis patients
(Blackwell Publishing Ltd, 2019) Bhawana Singh; Siddharth Sankar Singh; Shyam Sundar
Aim: Iron is key ingredient for immunosurveillance and host-pathogen interaction. Intracellular pathogen steals the iron from the host, but how parasite orchestrates iron acquisition and affects immune responses remains controversial. We aimed to study the iron homoeostasis in visceral leishmaniasis (VL) and its influence on immune machinery. Methods and Results: This study was performed on purified monocytes and T cells, peripheral blood mononuclear cells and splenic aspirates for transcriptional analyses of iron homoeostasis (hepcidin, DMT1, transferrin receptor, ferroportin) and immune modulations (IFN-γ, HLA-DR, IL-10, iNOS, IL-6). Serum/plasma was used for determination of iron, total/transferrin iron-binding capacity and anti-leishmania antibody titres in cases. We report that VL-induced perturbation in iron homoeostasis may cause immune dysfunctions. VL cases had decreased iron uptake by transferrin-dependent and transferrin-independent routes while elevated hepcidin, degraded sole iron exporter ferroportin. Therefore, it appears that perturbation in iron homoeostasis has essential role in HLA-DR mediated antigen presentation and innate armoury by downregulating iNOS as well as altering IFN-γ, IL-6 and IL-10 profiles. Conclusion: The iron homoeostasis by hepcidin can serve as one of the crucial determinants for regulating immune cell signalling; therefore, targeting iron metabolism, specifically hepcidin alone or in combination with agonists, can serve to clear infection. © 2018 John Wiley & Sons Ltd
HLA-DR Class II expression on myeloid and lymphoid cells in relation to HLA-DRB1 as a genetic risk factor for visceral leishmaniasis
(Blackwell Publishing Ltd, 2019) Bhawana Singh; Michaela Fakiola; Medhavi Sudarshan; Joyce Oommen; Siddharth Sankar Singh; Shyam Sundar; Jenefer M. Blackwell
Genetic variation at HLA-DRB1 is a risk factor for visceral leishmaniasis (VL) caused by Leishmania donovani. The single nucleotide polymorphism rs9271252 upstream of the DRB1 gene provides a perfect tag for protective versus risk HLA-DRB1 four-digit alleles. In addition to the traditional role of the membrane-distal region of HLA class II molecules in antigen presentation and CD4 T-cell activation, the membrane-proximal region mediates ‘non-traditional’ multi-functional activation, differentiation, or death signals, including in DR-expressing T cells. To understand how HLA-DR contributes to disease pathogenesis, we examined expression at the protein level in circulating myeloid (CD14+, CD16+) and lymphoid (CD4+, CD8+, CD19+) cells of VL patients (pre- and post-treatment) compared with endemic healthy controls (EHC). Although DR expression is reduced in circulating myeloid cells in active disease relative to EHC and post-treatment groups, expression is enhanced on CD4+ DR+ and CD8+ DR+ T cells consistent with T-cell activation. Cells of all myeloid and lymphoid populations from active cases were refractory to stimulation of DR expression with interferon-γ (IFN-γ). In contrast, all populations except CD19+ B cells from healthy blood bank controls showed enhanced DR expression following IFN-γ stimulation. The rs9271252 genotype did not impact significantly on IFN-γ-activated DR expression in myeloid, B or CD8+ T cells, but CD4+ T cells from healthy individuals homozygous for the risk allele were particularly refractory to activated DR expression. Further analysis of DR expression on subsets of CD4+ T cells regulating VL disease could uncover additional ways in which pleiotropy at HLA DRB1 contributes to disease pathogenesis. © 2018 John Wiley & Sons Ltd
Human IL-10–producing Th1 cells exhibit a molecular signature distinct from Tr1 cells in malaria
(American Society for Clinical Investigation, 2023) Chelsea L. Edwards; Susanna S. Ng; Fabian de Labastida Rivera; Dillon Corvino; Jessica A. Engel; Marcela Montes de Oca; Luzia Bukali; Teija C.M. Frame; Patrick T. Bunn; Shashi Bhushan Chauhan; Siddharth Sankar Singh; Yulin Wang; Jinrui Na; Fiona H. Amante; Jessica R. Loughland; Megan S.F. Soon; Nicola Waddell; Pamela Mukhopadhay; Lambros T. Koufariotis; Rebecca L. Johnston; Jason S. Lee; Rachel Kuns; Ping Zhang; Michelle J. Boyle; Geoffrey R. Hill; James S. McCarthy; Rajiv Kumar; Christian R. Engwerda
Control of intracellular parasites responsible for malaria requires host IFN-γ+T-bet+CD4+ T cells (Th1 cells) with IL-10 produced by Th1 cells to mitigate the pathology induced by this inflammatory response. However, these IL-10–producing Th1 (induced type I regulatory [Tr1]) cells can also promote parasite persistence or impair immunity to reinfection or vaccination. Here, we identified molecular and phenotypic signatures that distinguished IL-10–Th1 cells from IL-10+Tr1 cells in Plasmodium falciparum–infected people who participated in controlled human malaria infection studies, as well as C57BL/6 mice with experimental malaria caused by P. berghei ANKA. We also identified a conserved Tr1 cell molecular signature shared between patients with malaria, dengue, and graft-versus-host disease. Genetic manipulation of primary human CD4+ T cells showed that the transcription factor cMAF played an important role in the induction of IL-10, while BLIMP-1 promoted the development of human CD4+ T cells expressing multiple coinhibitory receptors. We also describe heterogeneity of Tr1 cell coinhibitory receptor expression that has implications for targeting these molecules for clinical advantage during infection. Overall, this work provides insights into CD4+ T cell development during malaria that offer opportunities for creation of strategies to modulate CD4+ T cell functions and improve antiparasitic immunity. © 2023 American Society for Clinical Investigation. All rights reserved.
Increased amphiregulin expression by CD4+ T cells from individuals with asymptomatic Leishmania donovani infection
(John Wiley and Sons Inc, 2022) Siddharth Sankar Singh; Shashi Bhushan Chauhan; Susanna SS Ng; Dillon Corvino; Fabian de Labastida Rivera; Jessica A Engel; Nic Waddell; Pamela Mukhopadhay; Rebecca L Johnston; Lambros T Koufariotis; Susanne Nylen; Om Prakash Singh; Christian R Engwerda; Rajiv Kumar; Shyam Sundar
Objectives: There is an urgent need to be able to identify individuals with asymptomatic Leishmania donovani infection, so their risk of progressing to VL and transmitting parasites can be managed. This study examined transcriptional markers expressed by CD4+ T cells that could distinguish asymptomatic individuals from endemic controls and visceral leishmaniasis (VL) patients. Methods: CD4+ T cells were isolated from individuals with asymptomatic L. donovani infection, endemic controls and VL patients. RNA was extracted and RNAseq employed to identify differentially expressed genes. The expression of one gene and its protein product during asymptomatic infection were evaluated. Results: Amphiregulin (AREG) was identified as a distinguishing gene product in CD4+ T cells from individuals with asymptomatic L. donovani infection, compared to VL patients and healthy endemic control individuals. AREG levels in plasma and antigen-stimulated whole-blood assay cell culture supernatants were significantly elevated in asymptomatic individuals, compared to endemic controls and VL patients. Regulatory T (Treg) cells were identified as an important source of AREG amongst CD4+ T-cell subsets in asymptomatic individuals. Conclusion: Increased Treg cell AREG expression was identified in individuals with asymptomatic L. donovani infection, suggesting the presence of an ongoing inflammatory response in these individuals required for controlling infection and that AREG may play an important role in preventing inflammation-induced tissue damage and subsequent disease in asymptomatic individuals. © 2022 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.
Interleukin 2 is an Upstream Regulator of CD4+ T Cells from Visceral Leishmaniasis Patients with Therapeutic Potential
(Oxford University Press, 2019) Shashi Bhushan Chauhan; Rebecca Faleiro; Rajiv Kumar; Susanna Ng; Bhawana Singh; Om Prakash Singh; Siddharth Sankar Singh; Fiona Amante; Fabian De Labastida Rivera; Madhukar Rai; Jaya Chakravarty; David Sacks; Susanne Nylen; Shyam Sundar; Christian Engwerda
Control of visceral leishmaniasis (VL) caused by Leishmania donovani requires interferon-γproduction by CD4+ T cells. In VL patients, antiparasitic CD4+ T-cell responses are ineffective for unknown reasons. In this study, we measured the expression of genes associated with various immune functions in these cells from VL patients and compared them to CD4+ T cells from the same patients after drug treatment and from endemic controls. We found reduced GATA3, RORC, and FOXP3 gene expression in CD4+ T cells of VL patients, associated with reduced Th2, Th17, and FOXP3+CD4+ T regulatory cell frequencies in VL patient blood. Interleukin 2 (IL-2) was an important upstream regulator of CD4+ T cells from VL patients, and functional studies demonstrated the therapeutic potential of IL-2 for improving antiparasitic immunity. Together, these results provide new insights into the characteristics of CD4+ T cells from VL patients that can be used to improve antiparasitic immune responses. © 2019 The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.
The NK cell granule protein NKG7 regulates cytotoxic granule exocytosis and inflammation
(Nature Research, 2020) Susanna S. Ng; Fabian De Labastida Rivera; Juming Yan; Dillon Corvino; Indrajit Das; Ping Zhang; Rachel Kuns; Shashi Bhushan Chauhan; Jiajie Hou; Xian-Yang Li; Teija C. M. Frame; Benjamin A. McEnroe; Eilish Moore; Jinrui Na; Jessica A. Engel; Megan S. F. Soon; Bhawana Singh; Andrew J. Kueh; Marco J. Herold; Marcela Montes de Oca; Siddharth Sankar Singh; Patrick T. Bunn; Amy Roman Aguilera; Mika Casey; Matthias Braun; Nazanin Ghazanfari; Shivangi Wani; Yulin Wang; Fiona H. Amante; Chelsea L. Edwards; Ashraful Haque; William C. Dougall; Om Prakash Singh; Alan G. Baxter; Michele W. L. Teng; Alex Loukas; Norelle L. Daly; Nicole Cloonan; Mariapia A. Degli-Esposti; Jude Uzonna; William R. Heath; Tobias Bald; Siok-Keen Tey; Kyohei Nakamura; Geoffrey R. Hill; Rajiv Kumar; Shyam Sundar; Mark J. Smyth; Christian R. Engwerda
Immune-modulating therapies have revolutionized the treatment of chronic diseases, particularly cancer. However, their success is restricted and there is a need to identify new therapeutic targets. Here, we show that natural killer cell granule protein 7 (NKG7) is a regulator of lymphocyte granule exocytosis and downstream inflammation in a broad range of diseases. NKG7 expressed by CD4+ and CD8+ T cells played key roles in promoting inflammation during visceral leishmaniasis and malaria—two important parasitic diseases. Additionally, NKG7 expressed by natural killer cells was critical for controlling cancer initiation, growth and metastasis. NKG7 function in natural killer and CD8+ T cells was linked with their ability to regulate the translocation of CD107a to the cell surface and kill cellular targets, while NKG7 also had a major impact on CD4+ T cell activation following infection. Thus, we report a novel therapeutic target expressed on a range of immune cells with functions in different immune responses. © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.
The phenotype of circulating neutrophils during visceral leishmaniasis
(American Society of Tropical Medicine and Hygiene, 2017) Smriti Sharma; Shweta Srivastva; Richard E. Davis; Siddharth Sankar Singh; Rajiv Kumar; Susanne Nylén; Mary E. Wilson; Shyam Sundar
Visceral leishmaniasis (VL) is a chronic parasitic disease associated with suppressed T cell responses. Although parasites reside intracellularly in macrophages during chronic VL, neutrophils are the first host cell to in filtrate the infection site and phagocytose the parasite. Subsets of neutrophils with unusual characteristics have been documented in human VL, but whether the total neutrophil population is a berrant during disease is not known. Therefore, we examined phenotypic characteristics of unfractionated polymorphonuclear leukocyte (neutrophils) from subjects with active VL, and compared these with neutrophils from healthy controls or subjects who have been treated for VL. The data showed decreased mRNA and diminished amounts of the neutrophil chemoattractant CXCL8 (interleukin [IL]-8), increased IL-10 mRNA and protein, and elevated transcripts encoding arginase-1, which is involved in suppressing T cell responses. Neutrophils from VL subjects showed enhanced capacity to phagocytose Leishmania spp. promastigotes. The results suggest that neutrophils may contribute to immunosuppression in subjects with active VL. © Copyright 2017 by The American Society of Tropical Medicine and Hygiene.
Type I Interferons Suppress Anti-parasitic Immunity and Can Be Targeted to Improve Treatment of Visceral Leishmaniasis
(Elsevier B.V., 2020) 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
CD4+ T cells are critical for control of intracellular parasites such as Leishmania donovani. Kumar et al. show that type I interferons (IFNs) suppress Th1 cells and promote IL-10-producing CD4+ T cells during visceral leishmaniasis (VL). Thus, manipulation of type I IFN signaling may improve disease outcome in VL patients. © 2020 The Authors; 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. © 2020 The Authors