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Immunomodulatory Effects of Azithromycin Revisited: Potential Applications to COVID-19

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Immunomodulatory Effects of Azithromycin Revisited: Potential Applications to COVID-19 University of Kentucky UKnowledge Pharmaceutical Sciences Faculty Publications Pharmaceutical Sciences 2-12-2021 Immunomodulatory Effects of Azithromycin Revisited: Potential Applications to COVID-19 Vincent J. Venditto University of Kentucky, [email protected] Dalia Haydar St. Jude Children’s Research Hospital Ahmed K. Abdel-Latif University of Kentucky, [email protected] John C. Gensel University of Kentucky, [email protected] See next page for additional authors Right click to open a feedback form in a new tab to let us know how this document benefits ou.y Follow this and additional works at: https://uknowledge.uky.edu/ps_facpub Part of the Medical Immunology Commons, and the Pharmacy and Pharmaceutical Sciences Commons Immunomodulatory Effects of Azithromycin Revisited: Potential Applications to COVID-19 Digital Object Identifier (DOI) https://doi.org/10.3389/fimmu.2021.574425 Notes/Citation Information Published in Frontiers in Immunology, v. 12, article 574425. © 2021 Venditto, Haydar, Abdel-Latif, Gensel, Anstead, Pitts, Creameans, Kopper, Peng and Feola This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Authors Vincent J. Venditto, Dalia Haydar, Ahmed K. Abdel-Latif, John C. Gensel, Michael I. Anstead, Michelle G. Pitts, Jarrod W. Creameans, Timothy J. Kopper, Chi Peng, and David J. Feola This review is available at UKnowledge: https://uknowledge.uky.edu/ps_facpub/157 REVIEW published: 12 February 2021 doi: 10.3389/fimmu.2021.574425 Immunomodulatory Effects of Azithromycin Revisited: Potential Applications to COVID-19 Vincent J. Venditto 1, Dalia Haydar 2, Ahmed Abdel-Latif 3, John C. Gensel 4, Michael I. Anstead 5, Michelle G. Pitts 1, Jarrod Creameans 6, Timothy J. Kopper 4, Chi Peng 3 and David J. Feola 6* 1 Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, United States, 2 Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children’s Research Hospital, Memphis, TN, United States, 3 Gill Heart Institute and Division of Cardiovascular Medicine, College of Medicine, University of Kentucky, Lexington, KY, United States, 4 Department of Physiology, Spinal Cord and Brain Injury Research Center, College of Medicine, University of Kentucky, Lexington, KY, United States, 5 Department of Pediatrics, College of Medicine, University of Kentucky, Lexington, KY, United States, 6 Department of Pharmacy Practice and Science, College of Pharmacy, University of Kentucky, Lexington, KY, United States Edited by: Amy Rasley, United States Department of Energy The rapid advancement of the COVID-19 pandemic has prompted an accelerated pursuit (DOE), United States to identify effective therapeutics. Stages of the disease course have been defined by Reviewed by: viral burden, lung pathology, and progression through phases of the immune response. Gaurav Gupta, NIIT University, India Immunological factors including inflammatory cell infiltration and cytokine storm have Maryam Dadar, been associated with severe disease and death. Many immunomodulatory therapies for Razi Vaccine and Serum Research Institute, Iran COVID-19 are currently being investigated, and preliminary results support the premise *Correspondence: of targeting the immune response. However, because suppressing immune mechanisms David J. Feola could also impact the clearance of the virus in the early stages of infection, therapeutic [email protected] success is likely to depend on timing with respect to the disease course. Azithromycin is Specialty section: an immunomodulatory drug that has been shown to have antiviral effects and potential This article was submitted to benefit in patients with COVID-19. Multiple immunomodulatory effects have been defined Microbial Immunology, for azithromycin which could provide efficacy during the late stages of the disease, a section of the journal Frontiers in Immunology including inhibition of pro-inflammatory cytokine production, inhibition of neutrophil influx, Received: 19 June 2020 induction of regulatory functions of macrophages, and alterations in autophagy. Here Accepted: 22 January 2021 we review the published evidence of these mechanisms along with the current clinical Published: 12 February 2021 use of azithromycin as an immunomodulatory therapeutic. We then discuss the potential Citation: Venditto VJ, Haydar D, Abdel-Latif A, impact of azithromycin on the immune response to COVID-19, as well as caution against Gensel JC, Anstead MI, Pitts MG, immunosuppressive and off-target effects including cardiotoxicity in these patients. Creameans J, Kopper TJ, Peng C and While azithromycin has the potential to contribute efficacy, its impact on the COVID-19 Feola DJ (2021) Immunomodulatory Effects of Azithromycin Revisited: immune response requires additional characterization so as to better define its role in Potential Applications to COVID-19. individualized therapy. Front. Immunol. 12:574425. doi: 10.3389/fimmu.2021.574425 Keywords: immunomodulation, COVID-19, azithromycin, inflammation, therapeutic Frontiers in Immunology | www.frontiersin.org 1 February 2021 | Volume 12 | Article 574425 Venditto et al. Azithromycin for COVID-19 INTRODUCTION COVID-19 AND CURRENT IMMUNOTHERAPY Azithromycin is administered to over 40 million patients annually for its antibacterial activity (1), but characterization Novel Coronaviruses of the immunomodulatory properties of the macrolide Coronaviruses (CoV) are enveloped, single stranded RNA viruses antimicrobials has expanded their use. Clinically, azithromycin capable of infecting a range of hosts including humans, with is used to treat bacterial infections of the upper respiratory the novel CoV’s resulting in potentially fatal lower respiratory tract, but has also been shown to improve lung function in tract infection (22). The three most significant CoV outbreaks subjects with various pulmonary pathologies, most notably to impact humans include SARS-CoV in 2002, Middle East in patients with cystic fibrosis (2–6). Mechanistic studies Respiratory Syndrome (MERS)-CoV in 2012, and most recently demonstrate immunomodulatory activity through the regulation SARS-CoV-2 in 2019. The interplay between viral diversity, of cellular processes involved in inflammation including NF- host species, and underlying clinical characteristics make CoV κB signaling (7–12), inflammasome activation (13, 14), and infections a challenge to predict, which is further compounded by autophagy flux (15, 16). Although azithromycin inhibits a the globalization and rapid escalation to pandemic levels. SARS- variety of pro-inflammatory pathways, it does not result in full CoV-2 is an enveloped virus consisting of a lipid bilayer and four immune suppression as is induced by glucocorticoids and other structural proteins, including spike (S), membrane (M), envelope immunosuppressive therapies. Rather, azithromycin exhibits (E), and nucleocapsid (N) proteins. The N protein is in complex immunomodulatory properties by shifting the inflammatory with single-stranded RNA on the interior of the virus, while M response, mainly in macrophages, toward one characterized and E are transmembrane proteins embedded in the lipid bilayer. by functional aspects of regulation and repair. These effects S protein is anchored in the lipid bilayer and forms a protein position azithromycin to have a profound effect on inflammatory corona that engages with target receptors for cellular entry (23). conditions in which the immune response contributes to Notably, SARS-CoV and SARS-CoV-2 enter cells after binding detrimental tissue damage, organ failure, and death. angiotensin converting enzyme 2 (ACE2) while MERS enters The emergence of severe acute respiratory syndrome (SARS)- through dipeptidyl peptidase 4 (DPP4) (24). Both receptors are coronavirus 2 (CoV-2) has thrust azithromycin into the expressed throughout the body and are upregulated in subjects spotlight due to early reports of improved outcomes in patients with comorbidities, leading to increased severity of infection in treated with azithromycin and hydroxychloroquine (17). The some subjects (25, 26). These characteristics lead to additional immunopathology of Coronavirus Disease 2019 (COVID-19) complications that compound the health outcomes in high risk that results from SARS-CoV-2 infection is highlighted by weak populations. At the time of the submission of this review, SARS- innate antiviral responses as a result of inadequate production of CoV-2 has infected over 90 million people across the globe and the antiviral cytokines (type I and type III interferons), and robust has contributed to over 1,950,000 deaths as the global pandemic pro-inflammatory responses with high levels of chemokine continues to evolve. and cytokine expression (18). In some patients infected with SARS-CoV-2, pulmonary interstitial fibrosis results due to an Stages of the Immune Response overactive immune response to the infection (19). Furthermore, COVID-19 has loosely been characterized to be comprised of 3 severe cases of COVID-19 are characterized by cytokine storm immunological stages. In the first stage, an interferon response and acute respiratory distress syndrome (ARDS)
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