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Targeting the IL33–NLRP3 Axis Improves Therapy for Experimental Cerebral Malaria

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Targeting the IL33–NLRP3 axis improves therapy for experimental cerebral malaria Patrick Strangwarda, Michael J. Haleya,1, Manuel G. Albornoza,1, Jack Barringtona,1, Tovah Shawa, Rebecca Dookiea, Leo Zeefa, Syed M. Bakera, Emma Wintera, Te-Chen Tzengb, Douglas T. Golenbockb, Sheena M. Cruickshanka, Stuart M. Allana, Alister Craigc, Foo Y. Liewd,e, David Brougha,2,3, and Kevin N. Coupera,2,3 aSchool of Biological Sciences, Faculty of Biology, Medicine, and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PT, United Kingdom; bDivision of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605; cDepartment of Parasitology, Liverpool School of Tropical Medicine, Liverpool L3 5QA, United Kingdom; dDepartment of Immunology, Institute of Infection, Immunity, and Inflammation, University of Glasgow, Glasgow G12 8TA, United Kingdom; and eSchool of Biology and Basic Medical Sciences, Soochow University, 215006 Suzhou, China Edited by Michael B. A. Oldstone, The Scripps Research Institute, La Jolla, CA, and approved June 4, 2018 (received for review January 30, 2018) Cerebral malaria (CM) is a serious neurological complication caused recovery by activating the brain endothelium, causing permeability by Plasmodium falciparum infection. Currently, the only treatment of the blood–brain barrier, activation of astrocytes and microglia, for CM is the provision of antimalarial drugs; however, such treat- disruption of neuronal signaling, and recruitment of circulating ment by itself often fails to prevent death or development of neu- leukocytes (1, 7–9). All of these events have been observed in rological sequelae. To identify potential improved treatments for brains of individuals with fatal CM (1, 6–9). In particular, it is CM, we performed a nonbiased whole-brain transcriptomic time- believed that cerebrovascular dysfunction is a critical pathological course analysis of antimalarial drug chemotherapy of murine process in CM development and fatal outcome (1, 7, 9). There- experimental CM (ECM). Bioinformatics analyses revealed IL33 as fore, intracerebral inflammatory responses at time of treatment a critical regulator of neuroinflammation and cerebral pathology may prevent re-establishment of brain homeostasis, leading to the that is down-regulated in the brain during fatal ECM and in the failure of antimalarial drug treatment. acute period following treatment of ECM. Consistent with this, ad- In this study, to identify immune candidates for therapy of ministration of IL33 alongside antimalarial drugs significantly im- CM, we optimized a preclinical model of Plasmodium berghei proved the treatment success of established ECM. Mechanistically, (Pb) ANKA-induced murine experimental cerebral malaria IL33 treatment reduced inflammasome activation and IL1β produc- (ECM) (10) where antimalarial drug treatment of established tion in microglia and intracerebral monocytes in the acute recovery ECM leads to suboptimal recovery, associated with significant period following treatment of ECM. Moreover, treatment with the mortality and development of severe cerebral pathology. Using NLRP3-inflammasome inhibitor MCC950 alongside antimalarial this infection–drug cure model of ECM, we have performed a drugs phenocopied the protective effect of IL33 therapy in improv- nonbiased whole-brain RNA-seq time-course analysis during ing the recovery from established ECM. We further showed that antimalarial drug chemotherapy. We subsequently identified IL1β release from macrophages was stimulated by hemozoin and antimalarial drugs and that this was inhibited by MCC950. Our re- Significance sults therefore demonstrate that manipulation of the IL33–NLRP3 axis may be an effective therapy to suppress neuroinflammation and improve the efficacy of antimalarial drug treatment of CM. Cerebral malaria (CM) is a neurological complication of malaria infection that, despite antimalarial drug treatment, results in fatality or neurodisability in approximately 25% of cases. Thus, malaria | IL33 | NLRP3 | inflammasome | inflammation there is an urgent clinical need to develop therapies that can improve the efficacy of antimalarial drugs to prevent or reverse erebral malaria (CM) is a severe manifestation of Plasmo- – cerebral pathology. Here, we show in an experimental mouse Cdium falciparum infection, which affects 2 3 million people model of CM (ECM) that IL33 administration can improve sur- each year, mainly young children in Africa (1). The only treatment vival and reduce pathology in the brain over antimalarial drugs for CM is antimalarial drugs, typically in the form of parenteral alone. Mechanistically, we demonstrate that IL33 enhances artesunate or quinine compounds. Such treatment fails to prevent recovery from ECM by inhibiting NLRP3 inflammasome-induced mortality in a quarter of CM patients, leading to the death of inflammatory responses within the brain. These results suggest ∼300,000 people each year (1–3). Moreover, up to 26% of indi- that IL33 and NLRP3 inflammasome inhibitors may be effective viduals develop residual neurological deficits following antima- adjunctive therapies for CM. larial drug treatment and recovery from CM (4, 5). Thus, CM remains a leading cause of mortality and neurodisability in trop- Author contributions: P.S., S.M.C., S.M.A., A.C., F.Y.L, D.B., and K.N.C. designed research; ical regions (1–5). Consequently, there is a critical clinical need for P.S., M.J.H., J.B., T.S., R.D., and E.W. performed research; T.-C.T., D.T.G., F.Y.L., and D.B. contributed new reagents/analytic tools; P.S., M.J.H., M.G.A., J.B., L.Z., S.M.B., E.W., and development of more effective therapies for CM that will enhance K.N.C. analyzed data; and P.S., M.J.H., D.B., and K.N.C. wrote the paper. the protective effects of antimalarial drugs. The authors declare no conflict of interest. The cerebral processes contributing to the pathophysiology This article is a PNAS Direct Submission. of CM and those that undermine recovery from the syndrome Published under the PNAS license. after antimalarial drug treatment are poorly understood (1, 6–8). Data deposition: The sequence reported in this paper has been deposited in the ArrayExpress However, there is a growing consensus that targeting the host database (accession no. E-MTAB-6474). proinflammatory immune response to infection may be an effec- 1M.J.H., M.G.A., and J.B. contributed equally to this work. tive strategy to enhance the antimalarial drug treatment success 2D.B. and K.N.C. contributed equally to this work. of CM (7, 8). Indeed, serological and/or cerebral spinal fluid 3To whom correspondence may be addressed. Email: [email protected] or concentrations of proinflammatory cytokines and chemokines, [email protected]. α β γ including TNF ,IL6,IL1 ,IFN-, and CXCL10, frequently cor- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. relate with the development of CM and, in some cases, the se- 1073/pnas.1801737115/-/DCSupplemental. verity of CM (7, 8). Proinflammatory processes may disrupt CM Published online June 28, 2018. 7404–7409 | PNAS | July 10, 2018 | vol. 115 | no. 28 www.pnas.org/cgi/doi/10.1073/pnas.1801737115 Downloaded by guest on September 30, 2021 IL33 as a key regulator of cerebral inflammatory pathways dur- Infecon No treatment (Veh) Veh Veh A AC D G ing fatal ECM and in the acute period after antimalarial drug 30 ** 1.0 10 treatment. Injection of IL33 along with antimalarial drugs sig- 20 s 0.5 nificantly improved the recovery of mice with established ECM, 5 *** AC 10 AC Parasites / field potentially through reduction of NLRP3-dependent inflamma- Haemorrhage / field Parasitemia (%) 0 0.0 AC some activation. Consistent with this, direct inhibition of the 0 Veh AC Veh NLRP3 inflammasome using the specific inhibitor MCC950 d7 d7 100 B Veh Veh phenocopied the protective capacity of IL33 in improving re- 80 *** E H 3 ** 3 ** covery from ECM. Overall, these data indicate that pharmaco- 60 – 40 2 2 s logical strategies targeting the IL33 NLRP3 axis could potentially Survival (%) 20 be beneficial for the treatment of CM. 0 AC 1 AC 1 Occlusion / field C 0 Axonal injury / field 0 25 # Results Veh AC Veh AC 20 d7 d7 Antimalarial Drugs Promote Suboptimal Recovery from Established 15 ECM Veh Veh ECM. To study the recovery from established malaria-induced 10 * F I 5 3 *** 2.5 ** & Behaviour Scale & Behaviour cerebral pathology, we adapted the conventional Pb ANKA Rapid Murine Coma 0 2.0 024681012143060 2 1.5 ECM model (10) to recapitulate the clinical settings associated Days post infecon 1.0 AC 1 AC with the treatment of CM. C57BL/6 mice infected with Pb 0.5 Myelinopathy / field ANKA were treated daily with the antimalarial drugs artesunate Oedema score / field 0 0.0 Veh AC Veh AC [the front line drug for treatment of severe malaria (2)] and d7 d7 chloroquine (as a representative quinine compound), both at 30 mg/kg, or vehicle alone. Treatment began at the onset of neu- Fig. 1. Antimalarial drug treatment promotes suboptimal recovery from rological dysfunction, as defined by a rapid murine coma and ECM. Mice were infected with Pb ANKA GFP and treated with artesunate behavior scale (RMCBS) score of ≤15 (11), on day 6 post in- and chloroquine (AC) or vehicle (Veh) at the onset of ECM. (A) Peripheral fection (d6) (SI Appendix,Fig.S1). parasitemia, (B) survival curves, and (C) RMCBS scores of mice after infection (d0) and drug treatment (gray box). (D–I) Brains were examined 16–24 h Peripheral parasitemia developed exponentially before rapidly + after treatment (d7) for (D)GFP parasites (green), costained with lectin reducing upon antimalarial drug treatment (Fig. 1A). Despite (red) and DAPI (blue); (E) erythrocyte-congested vessels indicative of he- their potent parasiticidal activity, administration of antimalarial mostasis (H&E); (F) extravascular IgG indicative of vasogenic edema (DAB drugs [artesunate and chloroquine (AC)] failed to prevent counterstained with hematoxylin); (G) hemorrhage (H&E); (H) β-APP accu- mortality in ∼25% of mice (Fig.
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    TITLE Loss-Of-Function Mutations in SERPINB8

    TITLE Loss-of-function mutations in SERPINB8 linked to exfoliative ichthyosis with impaired mechanical stability of intercellular adhesions AUTHOR LIST Manuela Pigors,1 Ofer Sarig,2 Lisa Heinz,3 Vincent Plagnol,4 Judith Fischer,3 Janan Mohamad,2 Natalia Malchin,2 Shefali Rajpopat,1 Monia Kharfi,5 Giles G. Lestringant,6 Eli Sprecher,2 David P. Kelsell,1,7,* and Diana C. Blaydon1,7,* AFFILIATIONS 1Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, United Kingdom 2Department of Dermatology, Tel Aviv Sourasky Medical Center, 64239 Tel Aviv, Israel 3Institute of Human Genetics, University Medical Center Freiburg, 79106 Freiburg, Germany 4University College London Genetics Institute, London WC1E 6BT, United Kingdom 5Department of Dermatology, Charles Nicolle Hospital, 1006 Tunis, Tunisia 6Consultant Dermatologist (retired), British Ministry of Defence, London SW1A 2HB, United Kingdom. 7These authors contributed equally to this work and are joint senior authors *CORRESPONDENCE [email protected] [email protected] 1 ABSTRACT SERPINS comprise a large and functionally diverse family of serine protease inhibi- tors. Here, we report three unrelated families with loss-of-function mutations in SER- PINB8 in association with an autosomal recessive form of exfoliative ichthyosis. Whole exome sequencing of affected individuals from a consanguineous Tunisian family and a large Israeli family revealed a homozygous frameshift mutation, c.947delA; p.Lys316Serfs*90, and a nonsense mutation, c.850C>T, p.Arg284*, re- spectively. These two mutations are located in the last exon of SERPINB8 and, hence, would not be expected to lead to nonsense-mediated decay of the mRNA, nonetheless, both mutations are predicted to lead to loss of the reactive site loop of SERPINB8, which is crucial for forming the SERPINB8-protease complex.
  • Downloaded from the Broad Insti- Chromosomal Duplications Generated the Gene Clusters at Tute

    Downloaded from the Broad Insti- Chromosomal Duplications Generated the Gene Clusters at Tute

    BMC Genomics BioMed Central Research article Open Access Analysis of vertebrate genomes suggests a new model for clade B serpin evolution Dion Kaiserman and Phillip I Bird* Address: Department of Biochemistry & Molecular Biology, Monash University, Clayton, Victoria, Australia Email: Dion Kaiserman - [email protected]; Phillip I Bird* - [email protected] * Corresponding author Published: 23 November 2005 Received: 16 September 2005 Accepted: 23 November 2005 BMC Genomics 2005, 6:167 doi:10.1186/1471-2164-6-167 This article is available from: http://www.biomedcentral.com/1471-2164/6/167 © 2005 Kaiserman and Bird; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background: The human genome contains 13 clade B serpin genes at two loci, 6p25 and 18q21. The three genes at 6p25 all conform to a 7-exon gene structure with conserved intron positioning and phasing, however, at 18q21 there are two 7-exon genes and eight genes with an additional exon yielding an 8-exon structure. Currently, it is not known how these two loci evolved, nor which gene structure arose first – did the 8-exon genes gain an exon, or did the 7-exon genes lose one? Here we use the genomes of diverse vertebrate species to plot the emergence of clade B serpin genes and to identify the point at which the two genomic structures arose.