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Leishmania Donovani Exploits Tollip, a Multitasking Protein, to Impair TLR/IL-1R Signaling for Its Survival in the Host

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Leishmania donovani Exploits Tollip, a Multitasking Protein, To Impair TLR/IL-1R Signaling for Its Survival in the Host This information is current as Naveen Parmar, Pragya Chandrakar, Preeti Vishwakarma, of September 30, 2021. Kavita Singh, Kalyan Mitra and Susanta Kar J Immunol 2018; 201:957-970; Prepublished online 15 June 2018; doi: 10.4049/jimmunol.1800062 http://www.jimmunol.org/content/201/3/957 Downloaded from References This article cites 46 articles, 12 of which you can access for free at: http://www.jimmunol.org/content/201/3/957.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 30, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2018 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Leishmania donovani Exploits Tollip, a Multitasking Protein, To Impair TLR/IL-1R Signaling for Its Survival in the Host Naveen Parmar,*,† Pragya Chandrakar,*,† Preeti Vishwakarma,*,† Kavita Singh,‡ Kalyan Mitra,†,‡ and Susanta Kar*,† IL-1R/TLR signaling plays a significant role in sensing harmful foreign pathogens and mounting effective innate and adaptive immune responses. However, the precise mechanism by which Leishmania donovani, an obligate intramacrophagic pathogen, breaches IL-1R/TLR signaling and host-protective immunity remains obscure. In this study, we report the novel biphasic role of Toll-interacting protein (Tollip), a negative regulator of the IL-1R/TLR pathway, in the disease progression of experimental visceral leishmaniasis. We observed that during early hours of infection, L. donovani induced phosphorylation of IRAK-1, resulting in the release of Tollip from the IL-1R–associated kinase (IRAK)-1 complex in J774 macrophages, which then acted as an endocytic adaptor on cell surface IL-1R1 and promoted its lysosomal degradation. In the later stage, Tollip shuttled back to Downloaded from IRAK-1, thereby inhibiting IRAK-1 phosphorylation in association with IRAK-M to neutralize downstream TLR signaling in infected macrophages. Moreover, during late infection, L. donovani enhanced nuclear translocation and recruitment of transcrip- tion factors early growth response protein 2, NF erythroid 2–related factor 2, and Ahr on Tollip promoter for its induction. Small interfering RNA–mediated silencing of Tollip in infected macrophages significantly enhanced NF-kB activation and induced host- defensive IL-12 and TNF-a synthesis, thereby reducing amastigote multiplication. Likewise, abrogation of Tollip in L. donovani– infected BALB/c mice resulted in STAT-1–, IRF-1–, and NF-kB–mediated upregulation of host-protective cytokines and re- http://www.jimmunol.org/ duced organ parasite burden, thereby implicating its role in disease aggravation. Taken together, we conclude that L. donovani exploited the multitasking function of Tollip for its own establishment through downregulating IL-1R1/TLR signaling in macrophages. The Journal of Immunology, 2018, 201: 957–970. athogenicity of Leishmania donovani has been attributed members played an influential role in initiating host innate im- to the exploitation of host cellular machinery, which fa- mune responses and directing adaptive immune responses against cilitates favorable adaptation of parasites to the intra- invading foreign pathogens (1). However, L. donovani employed P by guest on September 30, 2021 cellular milieu of the innate immune sentinel cells such as numerous strategies to evade the first-line defense of the host by macrophages. Armed with a variety of pattern recognition re- manipulation of TLR and its downstream signaling components. ceptors, macrophages sense parasite surface molecules to trigger L. donovani hindered the TLR-mediated immune response at the appropriate host immune response. IL-1R/TLR superfamily multiple levels by exploiting host cellular proteins such as IL-1R– associated kinase (IRAK)-M (2), A20 (3), TRAF-3 (4), and phosphatases such as MKP-1, MKP-3, and PP2A (5). However, *Division of Parasitology, Council of Scientific and Industrial Research–Central the role of another Toll/IL-1R (TIR) superfamily member recep- Drug Research Institute, Lucknow 226031, India; †Academy of Scientific and Innovative Research, Anusandhan Bhawan, New Delhi 110001, India; and tor, IL-1R1, and its downstream signaling are poorly understood ‡Electron Microscopy Unit, Sophisticated Analytical Instrument Facility, Council during fatal visceral leishmaniasis (VL). IL-1 signaling plays an of Scientific and Industrial Research–Central Drug Research Institute, Lucknow important role in inflammation and early activation of host innate 226031, India immune response following foreign pathogens. Signal transduc- Received for publication January 16, 2018. Accepted for publication May 21, 2018. tion via IL-1R1 has a fundamental role in host defense against a This work was supported by Department of Science and Technology Grant SB/FT/ LS-310/2012, Council of Scientific and Industrial Research Grant CSIR NWP wide variety of pathogens, including Mycobacterium (6), Strep- BSC0114, and by Indian National Science Academy Grant SP/YSP/115/2015. N.P. tococcus (7), and Listeria monocytogenes (8). However, to prevent received a fellowship from the University Grants Commission (New Delhi), and P.C. irrelevant and adverse inflammatory responses, the IL-1R/TLR and P.V. are the recipients of fellowships from the Council of Scientific and Industrial Research (New Delhi). The funders had no role in study design, data collection and signaling pathway is tightly controlled by endogenous negative analysis, decision to publish, or preparation of the manuscript. regulators at multiple levels (9). This manuscript has Central Drug Research Institute Communication number 9670. Earlier reports suggested that a relationship exist between en- Address correspondence and reprint requests to Dr. Susanta Kar, Council of Scientific docytosis of ligand-activated receptors and further interaction with and Industrial Research–Central Drug Research Institute, Sector-10, Jankipuram downstream signaling molecules to continue signaling (10, 11). Extension, Sitapur Road, Lucknow 226031, Uttar Pradesh, India. E-mail address: [email protected] However, internalization followed by degradation in lysosomes is another fate of receptors that leads to attenuation of signaling and Abbreviations used in this article: BMDC, bone marrow–derived DC; ChIP, chroma- tin immunoprecipitation; CUE, coupling of ubiquitin to endoplasmic reticulum deg- is an extremely regulated process that involves recognition of radation; DC, dendritic cell; EEA1, early endosome Ag 1; Egr2, early growth ubiquitinated receptors by cargo proteins involved in their traf- response protein 2; IRAK, IL-1R–associated kinase; LAMP-1, lysosomal- associated membrane protein 1; LDU, Leishman–Donovan unit; LPG, lipophospho- ficking (12). Internalization of IL-1R1 from the plasma membrane glycan; Nrf2, NF erythroid 2–related factor 2; siRNA, small interfering RNA; TIR, played an important role in IL-1 signaling (13), and IL-1R1 also Toll/IL-1R; Tollip, Toll-interacting protein; TSS, transcription start site; VL, visceral undergoes monoubiquitnation before its degradation in lysosomes. leishmaniasis. The endosomal adaptor protein, Toll-interacting protein (Tollip), Copyright Ó 2018 by The American Association of Immunologists, Inc. 0022-1767/18/$35.00 is a multitasking regulator, as it not only participates in trafficking www.jimmunol.org/cgi/doi/10.4049/jimmunol.1800062 958 TOLLIP INHIBITS TLR/IL-1R1 SIGNALING IN VL and endosomal sorting of receptors such as TLR2, TLR4, and Parasite, cell culture conditions, and infection IL-1R1, but also in inhibiting IL/Toll/NF-kB signaling by L. donovani strain MHOM/IN/80/Dd8 was maintained as promastigotes in restricting phosphorylation of IRAK (14). Tollip is a multi- medium 199 (Sigma-Aldrich) supplemented with 10% heat-inactivated functional protein that contains the Tom1 binding domain at the FBS (Life Technologies) at 24 6 2˚C. J774 murine macrophage were N-terminal, a C2 domain that enables Tollip interaction with obtained from the National Centre for Cell Sciences (Pune, India) and were phosphoinositides, and the coupling of ubiquitin to endoplasmic grown as monolayers in RPMI 1640 medium (Sigma-Aldrich), supple- mented with 10% FBS, 100 U/ml penicillin, and 100 mg/ml streptomycin reticulum degradation (CUE) domain at the C-terminal. The (Invitrogen) in 5% CO2 atmosphere at 37˚C. Amastigotes of the MHOM/ CUE domain is responsible for associationofTolliptodifferent IN/80/Dd8 strain of L. donovani were freshly isolated from the spleen of cellular proteins, including IRAK-1, IL-1R1, TLR2, and TLR4. infected BALB/c mice. For in vitro studies, J774 macrophages were cul- Reports suggested that Tollip and its common variants negatively tured in petri dishes
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    American Trypanosomiasis and Leishmaniasis Trypanosoma cruzi Leishmania sp. American Trypanosomiasis History Oswaldo Cruz Trypanosoma cruzi - Chagas disease Species name was given in honor of Oswaldo Cruz -mentor of C. Chagas By 29, Chagas described the agent, vector, clinical symptoms Carlos Chagas - new disease • 16-18 million infected • 120 million at risk • ~50,000 deaths annually • leading cause of cardiac disease in South and Central America Trypanosoma cruzi Intracellular parasite Trypomastigotes have ability to invade tissues - non-dividing form Once inside tissues convert to amastigotes - Hela cells dividing forms Ability to infect and replicate in most nucleated cell types Cell Invasion 2+ Trypomatigotes induce a Ca signaling event 2+ Ca dependent recruitment and fusion of lysosomes Differentiation is initiated in the low pH environment, but completed in the cytoplasm Transient residence in the acidic lysosomal compartment is essential: triggers differentiation into amastigote forms Trypanosoma cruzi life cycle Triatomid Vectors Common Names • triatomine bugs • reduviid bugs >100 species can transmit • assassin bugs Chagas disease • kissing bugs • conenose bugs 3 primary vectors •Triatoma dimidiata (central Am.) •Rhodnius prolixis (Colombia and Venezuela) •Triatoma infestans (‘southern cone’ countries) One happy triatomid! Vector Distribution 4 principal vectors 10-35% of vectors are infected Parasites have been detected in T. sanguisuga Enzootic - in animal populations at all times Many animal reservoirs Domestic animals Opossums Raccoons Armadillos Wood rats Factors in Human Transmission Early defication - during the triatome bloodmeal Colonization of human habitats Adobe walls Thatched roofs Proximity to animal reservoirs Modes of Transmission SOURCE COMMENTS Natural transmission by triatomine bugs Vector through contamination with infected feces. A prevalent mode of transmission in urban Transfusion areas.