Caspases in COVID-19 Disease and Sequela and the Therapeutic Potential of Caspase Inhibitors

Currently, there is no effective vaccine and only one FDA approved early-stage therapy against SARS-CoV-2 infection as an indication to prevent disease progression. Cellular caspases play a role in the pathophysiology of a number of disorders that the co-morbid conditions seen in severe COVID-19 disease. In this study, we assessed transcriptional states of caspases in blood cells from COVID-19 patients. Gene expression levels of select caspases were increased in in vitro SARS-CoV-2 infection models and single cell RNA-Seq data of blood from COVID-19 patients showed a distinct caspase expression in T cells, neutrophils, and dendritic cells. Flow cytometric evaluation of CD4 T cells showed up-regulation of caspase-1 in hospitalized COVID-19 patients compared to unexposed controls. Convalescent COVID-19 patients with lingering symptoms (“long haulers”) showed persistent up-regulation of caspase-1 in CD4 T cells that was attenuated ex vivo following co-culture with a select pan-caspase inhibitor. Further, we observed elevated caspase-3 levels in red blood cells from COVID-19 patients compared to controls that were responsive to caspase inhibition. Our results expose an exuberant caspase response in COVID-19 that may facilitate immune-related pathological processes leading to severe outcomes. Pan-caspase inhibition could emerge as a therapeutic strategy to ameliorate or prevent severe COVID-19 outcomes. ### Competing Interest Statement None of the authors have any relevant conflict of interest to disclose with the exception of L.C.N. has received fees from Abbvie within the past year and has received compensation for serving on a scientific advisory board for Cytodyn for work unrelated to this project. All other authors declare no competing interests. ### Funding Statement None for the study. L.C.N. is supported by several NIH awards including from the National Institute of Mental Health (R01 MH112457) and National Institute of Allergy and Infectious Diseases (UM1 AI126617) BELIEVE Collaboratories. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Western IRB: 1285028 for Amerimmune S.U.N.Y. Downstate IRB 269846-10 for SUNY Downstate Medical Center All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data regarding the manuscript is available on request