key: cord-0860146-xiavt6is authors: Sanchez-Pernaute, Olga; Romero-Bueno, Fredeswinda I.; Selva-O’Callaghan, Albert title: Why choose cyclosporin A as first-line therapy in COVID-19 pneumonia() date: 2021-10-29 journal: Reumatol Clin (Engl Ed) DOI: 10.1016/j.reumae.2020.03.005 sha: 2578e74daf0bc359aeb4eeff8cfd78d6371aed1d doc_id: 860146 cord_uid: xiavt6is nan expression of interferons and cytokines, which are pivotal for an effective antiviral response. 3 Mitochondrial function is thus essential for the antiviral defense, while these organelles also need to provide for the increased energetic needs of infected cells. This fact points to mitochondrial failure as the mechanism unchaining severe forms of COVID-19 infection. 4 In brief, infected cells are exposed to an overload of nascent polypeptides, transcriptional machinery and by-products of helicases activation, altogether jeopardizing maintenance of protein folding and triggering cell and mitochondrial stress. 5, 6 In addition, COVID-19 genome polyadelnylation at the cytosol could waste adenine deposits and challenge mitochondrial permeability transition pore (MPTP). Ultimately, mitochondrial proteostasis collapse would drive caspases activation and irreversible cell damage. According to available literature, calcineurin inhibitors could confer protection from these pathogenic processes. Briefly, these compounds help restore the unfolded-protein response (UPR) at the cytosol, and may in this way rescue cells from necrosis. 7 In addition, upon targeting cyclophilin D, cyclosporin A inhibits MPTP opening, activates mitochondrial UPR (mtUPR) and prevents mitochondrial failure. 8, 9 Moreover, through this mechanism, cyclosporin A has shown cardioprotective effects in patients with myocardial infarction. 10 Of interest, there is a subtype of clinically amyopathic dermatomyositis (CADM) identified by the presence of antibodies against melanoma differentiation activated protein 5 (MDA5), which is an RLR helicase and also the putative cytoplasmic receptor for COVID-19. Patients with MDA5 syndrome are prone to the development of rapidly progressive interstitial pneumonia and refractory respiratory failure. Even though MDA5 syndrome is a rare condition, its resemblance with the clinical features of CoV infections cannot go unnoticed. Notably, critically ill MDA5+ CADM patients can be rescued when a calcineurin inhibitor is administered early in the course of respiratory failure. 11 Finally, it should be emphasized that cyclosporin A has shown remarkable antiviral activities in a variety of RNA viruses, including the family of betacoronavirus, which employ cyclophilins as chaperones and nuclear factor of activated T cells (NFAT) as a major signaling pathway. 12, 13 On the whole, we suggest that COVID-19 deadly action on host cells including pneumocytes and T lymphocytes, results from their failure to adapt to cell and mitochondrial stress, while dysfunctional macrophages remain as virus reservoir at the target tissue. According to this model, cyclosporin A could confer protection upstream of the cytokine storm in COVID-19 infected patients, a hypothesis which it is planned to be tested in a randomized clinical trial in the coming weeks. COVID-19: consider cytokine storm syndromes and immunosuppression Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective study Intracellular sensing of viral genomes and viral evasion Mitochondria in innate immune signaling Modulation of the unfolded protein response by the severe acute respiratory syndrome coronavirus spike protein The mitochondrial unfolded protein response, a conserved stress response pathway with implications in health and disease Suppression of NF-B by cyclosporin A and tacrolimus (FK506) via induction of the C/EBP family: implication for unfolded protein response A novel in vitro CypD-mediated p53 aggregation assay suggests a model for mitochondrial permeability transition by chaperone systems Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death Effect of cyclosporine on reperfusion injury in acute myocardial infarction Survival benefit associated with early cyclosporine treatment for dermatomyositis-associated interstitial lung disease The SARS-coronavirus-host interactome: identification of cyclophilins as target for pan-coronavirus inhibitors MERS-coronavirus replication induces severe in vitro cytopathology and is strongly inhibited by cyclosporin A or interferon-␣ treatment Callaghan b a Rheumatology Division