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G Model REUMA-1405; No. of Pages 2 ARTICLE IN PRESS Reumatol Clin. 2020;xxx(xx):xxx–xxx www.reumatologiaclinica.org Letter to the Editor Why Choose Cyclosporin A as First-line Therapy altogether jeopardizing maintenance of protein folding and trigger- in COVID-19 Pneumonia夽 ing cell and mitochondrial stress.5,6 In addition, COVID-19 genome polyadelnylation at the cytosol could waste adenine deposits and ¿Por qué elegir ciclosporina A como primera línea terapéutica challenge mitochondrial permeability transition pore (MPTP). Ulti- para la neumonía causada por COVID-19? mately, mitochondrial proteostasis collapse would drive caspases activation and irreversible cell damage. According to available lit- Dear Editor: erature, calcineurin inhibitors could confer protection from these pathogenic processes. Briefly, these compounds help restore the The use of immunosuppressive therapies in COVID-19 infection unfolded-protein response (UPR) at the cytosol, and may in this way is a recently raised topic which comes to fill an unmet need in the rescue cells from necrosis.7 In addition, upon targeting cyclophilin management of the patients.1 Intriguingly, not only COVID-19 but D, cyclosporin A inhibits MPTP opening, activates mitochondrial also SARS and MERS CoVs – all members of the Betacoronavirus UPR (mtUPR) and prevents mitochondrial failure.8,9 Moreover, genus – associate to an increased risk of respiratory distress syn- through this mechanism, cyclosporin A has shown cardioprotective drome. Already in patients with SARS-CoV, the development of effects in patients with myocardial infarction.10 respiratory failure was thought to be the consequence of a vigor- Of interest, there is a subtype of clinically amyopathic der- ous innate immune response, while effectiveness of tocilizumab matomyositis (CADM) identified by the presence of antibodies in COVID-19 infected patients also supports the participation of a against melanoma differentiation activated protein 5 (MDA5), cytokine storm in severe phenotypes.1,2 A factor underlying this which is an RLR helicase and also the putative cytoplasmic explosive response could be the capacity of betacoronaviruses receptor for COVID-19. Patients with MDA5 syndrome are prone to invade immune-competent cells, particularly macrophages, to the development of rapidly progressive interstitial pneu- thereby hijacking the major drivers of innate immune responses. monia and refractory respiratory failure. Even though MDA5 Nonetheless, targeting pro-inflammatory cytokines is neither the syndrome is a rare condition, its resemblance with the clin- sole nor the first-line immunomodulatory approach in combat- ical features of CoV infections cannot go unnoticed. Notably, ing the infection. As represented in the figure, complex virus-host critically ill MDA5+ CADM patients can be rescued when a cal- cell interactions providing opportunities for therapeutics should be cineurin inhibitor is administered early in the course of respiratory regarded (Fig. 1). failure.11 Betacoronaviruses replicate and carry out transcriptional activ- Finally, it should be emphasized that cyclosporin A has shown ities at the cell cytosol, where the viral genome is detected remarkable antiviral activities in a variety of RNA viruses, including by RIG-1 like receptor (RLR) helicases. Upon binding of vRNA, the family of betacoronavirus, which employ cyclophilins as chap- RLR activate mitochondrial antiviral proteins (MAVS). These in erones and nuclear factor of activated T cells (NFAT) as a major turn trigger phosphorylation of transcription factors and gene signaling pathway.12,13 expression of interferons and cytokines, which are pivotal for On the whole, we suggest that COVID-19 deadly action on host an effective antiviral response.3 Mitochondrial function is thus cells including pneumocytes and T lymphocytes, results from their essential for the antiviral defense, while these organelles also failure to adapt to cell and mitochondrial stress, while dysfunc- need to provide for the increased energetic needs of infected tional macrophages remain as virus reservoir at the target tissue. cells. This fact points to mitochondrial failure as the mechanism According to this model, cyclosporin A could confer protection unchaining severe forms of COVID-19 infection.4 In brief, infected upstream of the cytokine storm in COVID-19 infected patients, a cells are exposed to an overload of nascent polypeptides, tran- hypothesis which it is planned to be tested in a randomized clinical scriptional machinery and by-products of helicases activation, trial in the coming weeks. 夽 All authors have contributed to the conception of the manuscript, have revised it critically, have approved the final version and agree to be accountable for all aspects of the work. https://doi.org/10.1016/j.reuma.2020.03.001 1699-258X/© 2020 Elsevier España, S.L.U. and Sociedad Española de Reumatologı́a y Colegio Mexicano de Reumatologı́a. All rights reserved. Please cite this article in press as: Sanchez-Pernaute O, et al. Why Choose Cyclosporin A as First-line Therapy in COVID-19 Pneumonia. Reumatol Clin. 2020. https://doi.org/10.1016/j.reuma.2020.03.001 G Model REUMA-1405; No. of Pages 2 ARTICLE IN PRESS 2 Letter to the Editor / Reumatol Clin. 2020;xxx(xx):xxx–xxx Fig. 1. The graphic represents a pathogenic model of 2019-nCoV considering different virus-host cell interactions. The virus entry, replication, assembly and shedding indicating infectivity are shown at the left, while the right side displays the innate antiviral response characterized by an interferon signature. The center of the figure represents intracellular events unchained by the presence of the virus, driving cell and mitochondrial stress and eventually ending in hypoxic damage. The sites of action of different immunomodulatory drugs are marked. ACE2: angiotensin converting enzyme 2, ANT: adenine nucleotide translocation, CARD: caspase activation and recruitment domains, CQ: chloroquine, CyD: cyclophilin D, ER: endoplasmic reticulum, FK506: tacrolimus, HSR: heat shock response (also unfolded-protein response of the cytosol), IFN: interferon, IRF: interferon regulatory factor, iJAK: inhibitor of Janus kinases, MAS: macrophage activation syndrome, MAVS: mitochondrial antiviral proteins, MDA5: melanoma differentiation-activated protein 5, mtUPR: mitochondrial unfolded-protein response, NF␬ B: transcriptional activator kappa B, polyA: polyadenylated, PTM: postranslational modifications, RIG-1: retinoic acid inducible gene 1, RLR: RIG-1-like receptors, Th: T helper lymphocytes, TCZ: tocilizumab, vRNA: viral RNA. References 10. Piot C, Croisille P, Staat P, Thibault H, Rioufol G, Mewton N, et al. Effect of cyclosporine on reperfusion injury in acute myocardial infarction. N Engl J Med. 1. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. COVID- 2008;359:473–81. 19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020, 11. Go DJ, Park JK, Kang EH, Kwon HM, Lee YJ, Song YW, et al. Survival benefit http://dx.doi.org/10.1016/S0140-6736(20)30628-0, published online March 13. associated with early cyclosporine treatment for dermatomyositis-associated 2. Peiris JS, Chu CM, Cheng VC. Clinical progression and viral load in a commu- interstitial lung disease. Rheumatol Int. 2016;36:125–31. nity outbreak of coronavirus-associated SARS pneumonia: a prospective study. 12. Pfefferle S, Schöpf J, Kögl M, Friedel CC, Müller MA, Carbajo-Lozoya J, Lancet. 2003;361:1767–72. et al. The SARS-coronavirus-host interactome: identification of cyclophilins 3. Lee HC, Chathuranga K, Lee JS. Intracellular sensing of viral genomes and viral as target for pan-coronavirus inhibitors. PLoS Pathog. 2011;7:e1002331, evasion. Exp Mol Med. 2019;51:1–13. http://dx.doi.org/10.1371/journal.ppat.1002331. 4. Banoth B, Cassel SL. Mitochondria in innate immune signaling. Transl Res. 13. de Wilde AH, Raj VS, Oudshoorn D, Bestebroer TM, van Nieuwkoop S, Limpens 2018;202:52–68. RWAL, et al. MERS-coronavirus replication induces severe in vitro cytopathology 5. Chan CP, Siu KL, Chin KT, Yuen KY, Zheng B, Jin DY. Modulation of the unfolded and is strongly inhibited by cyclosporin A or interferon-␣ treatment. J Gen Virol. protein response by the severe acute respiratory syndrome coronavirus spike 2013;94 Pt 8:1749–60. protein. J Virol. 2006;80:9279–87. 6. Jovaisaite V, Mouchiroud L, Auwerx J. The mitochondrial unfolded protein Olga Sanchez-Pernaute a,∗ , Fredeswinda I. Romero-Bueno a , response, a conserved stress response pathway with implications in health and Albert Selva-O’Callaghan b disease. J Exp Biol. 2014;217 Pt 1:137–43. 7. Du S, Hiramatsu N, Hayakawa K, Kasai A, Okamura M, Huang T, et al. Sup- a Rheumatology Division, Jiménez Díaz Foundation University pression of NF-␬ B by cyclosporin A and tacrolimus (FK506) via induction of the C/EBP family: implication for unfolded protein response. J Immunol. Hospital and Health Research Institute, Universidad Autónoma de 2009;182:7201–11. 8. Lebedev I, Nemajerova A, Foda ZH, Kornaj M, Tong M, Moll UM, et al. Madrid, Madrid, Spain b Department of Internal Medicine, Hospital Universitari Val A novel in vitro CypD-mediated p53 aggregation assay suggests a model for mitochondrial permeability transition by chaperone systems. J Mol Biol. d’Hebron, Universitat Autonoma de Barcelona, Barcelona, Spain 2016;428:4154–67. 9. Baines CP, Kaiser RA, Purcell NH, Blair NS, Osinska H, Hambleton MA, et al. Loss ∗ Corresponding author. of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature. 2005;434:658–62. E-mail address: osanchez@fjd.es (O. Sanchez-Pernaute). Please cite this article in press as: Sanchez-Pernaute O, et al. Why Choose Cyclosporin A as First-line Therapy in COVID-19 Pneumonia. Reumatol Clin. 2020. https://doi.org/10.1016/j.reuma.2020.03.001