SHOCK: Publish Ahead Print DOI: 10.1097/SHK.0000000000001610 Therapeutic Potential of B-1a Cellsin COVID-19 Monowar Aziz1*, Max Brenner1,2, Ping Wang1,2,3* 1Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, 09/22/2020 on BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3XGJiJSDa6kJtrA8GTJF1rNYg2oN5/iB8BU7ukdhpX3U= by http://journals.lww.com/shockjournal from Downloaded Downloaded Manhasset, NY from 2 http://journals.lww.com/shockjournal Department of Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY 3Department of Surgery, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3XGJiJSDa6kJtrA8GTJF1rNYg2oN5/iB8BU7ukdhpX3U= Running title:B-1a cells and COVID-19 Competing financial and/or non-financial interests: All authors declared that they have no competing interests. *Addresses for correspondence: Ping Wang, MD Professor and Chief Scientific Officer (CSO) The Feinstein Institutes for Medical Research 350 Community Dr., Manhasset, NY 11030 Tel: (516) 562-3411 Fax: (516) 562-2396 E-mail: [email protected] on Monowar Aziz, PhD 09/22/2020 Assistant Professor Center for Immunology and Inflammation The Feinstein Institutes for Medical Research 350 Community Dr., Manhasset, NY 11030 E-mail: [email protected] Copyright © 2020 by the Shock Society. Unauthorized reproduction of this article is prohibited. Abstract Coronavirus disease 2019 (COVID-19) is a life-threatening respiratory illnesscaused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).Its clinical presentation can vary from the asymptomatic state to acute respiratory distress syndrome (ARDS) and multi- organ dysfunction. Due to ourinsufficient understanding of its pathophysiology and lack of effective treatment,the morbidity and mortality ofsevere COVID-19 patients are high. Patients with COVID-19developARDSfueled byexaggerated neutrophil influx into the lungs and cytokine storm. B-1a cells represent a unique subpopulation of B lymphocytescritical for circulating natural antibodies, innate immunity,andimmunoregulation. These cells spontaneously produce natural IgM, interleukin (IL)-10, and granulocyte-monocytecolony stimulating factor (GM-CSF). Natural IgM neutralizes viruses and opsonizes bacteria, IL-10 attenuates the cytokine storm, and GM-CSF induces IgM production by B-1a cells in an autocrine manner. Indeed, B-1a cells have been shown to ameliorate influenza virus infection,sepsis, and pneumonia, all of which are similar to COVID-19. The recentdiscovery of B-1a cells in humans further reinforces their potentially critical role in the immune response against SARS-CoV-2 and their anticipated translational applications againstviral and microbial infections. Given that B-1a cells protect againstARDS via immunoglobulin production and theanti-COVID-19 effects ofconvalescent plasmatreatment, we recommend that studies be conducted to further examine the role of B-1a cells in the pathogenesis of COVID-19 and explore theirtherapeutic potential to treat COVID-19 patients. Key words: COVID-19; SARS-CoV-2; B-1a cells; IL-10; IgM; Neutrophils; ARDS;Sepsis Copyright © 2020 by the Shock Society. Unauthorized reproduction of this article is prohibited. Introduction Coronavirus disease 2019 (COVID-19) is an infectious disease caused by therecently identified and highly contagious severe acute respiratory syndrome coronavirus 2 (SARS-CoV- 2)(1). COVID-19 predominantly affectsthe respiratory systembecause the virus binds to cells expressingthe angiotensin-converting enzyme 2 (ACE2), which is abundantin the surface of type II alveolar cells of the lungs(2, 3). The virus uses itstransmembrane spike (S) glycoprotein to connect to ACE2 and penetrate the host cellwhere ithijacksthe cell machineryto multiply (2, 3).Many patients are asymptomatic or show only flu-like symptoms, but a substantial subset of COVID-19 patients develop severe pneumonia that often progresses toacute respiratory distress syndrome (ARDS)fueled by excessive neutrophilinfiltration and uncontrolled production of pro- inflammatory cytokines in the lungs(4-7). At the moment, the treatmentfor patients with COVID-19 is essentially supportive and symptomatic. There is a long list of drugs being evaluated and clinical trials being carried out(8), but none of them has yet proven to be a game changerfor patients withCOVID-19.Promising treatments include monoclonal antibodies against pro-inflammatory cytokines (8), immunoglobulin therapy,andantibody-containing convalescent plasmafrom recovered patients (8, 9). B-1a cells consist of a unique subset of B lymphocytes which play an early and key role in the innate immune response against viral, bacterial, and acute inflammatory diseases(10). These cells release polyreactivenatural IgM which non-specifically recognizesand neutralizes microbes(10-12). These cells also spontaneously produce the anti-inflammatory cytokines interleukin (IL)-10 and IL-35 and the immune bolsteringfactor granulocyte-monocyte colony stimulating factor (GM-CSF)(10, 13-15).B-1acells andsubpopulationswere originally described Copyright © 2020 by the Shock Society. Unauthorized reproduction of this article is prohibited. in the mouse and have also beenrecently identified in humans (16). B-1a cells ameliorate acute viral and bacterial infections in rodent models of influenza, polymicrobial sepsis, and pneumonia(10). B-1a cell therapyis able to mitigate the progression of these infections to ARDS,raising the possibility that B-1a cell therapymay alsoameliorate ARDS associated with COVID-19. Here, we review the protective effects ofB-1a cells in animal models of ARDScaused by viral and bacterialinfections with the caveat that sepsis and influenza may not accurately reflect the immune processes of COVID-19. We compare the pathophysiological and clinical aspects between bacterial sepsis and severe COVID-19 in Tables 1 and 2. Weanalyze the literature on B- 1a cells with a focus on the excessive neutrophil infiltration, abnormal neutrophil function, and the cytokine storm which have been described in numerous studies of patients with COVID-19. By comparing the existing B-1a cell literature and recent advances in the pathogenesis of COVID-19, we propose a novel perspective suggesting that treatment with B-1a cells may benefit patients with COVID-19.Since many clinical trials in sepsis have failed and almost no drug has yet been developed to treat sepsis patients,we acknowledge an obstacle of implementation of B-1a cells as a therapeutic candidate in COVID-19 because the beneficial outcomes of B-1a cells as reported here were mainly built upon sepsis data.For designing and conducting immunotherapies for COVID-19, the lessons learned from the sepsis clinical trials should be reminisced(17). COVID-19complications and pathophysiology While many infected individuals develop mild or moderate symptoms, a significant fraction of patients develop severe pneumonia, ARDS, multi-organ failure, and septic shock, not rarely resulting in death(4, 18). Cardiovascular complications may include heart failure, arrhythmias, Copyright © 2020 by the Shock Society. Unauthorized reproduction of this article is prohibited. myocarditis, and hypercoagulability(19). In addition, COVID-19 patients may sometimes develop liver injuryand acute kidney injury (20, 21). Its related neurologic manifestations include seizure, stroke, and encephalitis(22). The elderly are particularly vulnerable to severe SARS- CoV-2 infection, with a mortality rate higher than that of younger individuals, which may be due to a combination of immune senescence and the presence of co-morbidities(23, 24).However, following SARS-CoV-2 infection, patients of all ages can develop COVID-19, including children who sometimes developa severe systemic inflammation that can be lethal (25). SARS-CoV-2is a membrane-enveloped positive sense single-stranded RNAvirus of 50- 200 nm in diameter. It has four structural proteins: thespike(S), envelope (E), membrane (M), and nucleocapsid (N) proteins(26). The S protein has strong affinity for ACE2 on human cells,which it uses asa receptor to attach to and penetrate host cells, where it multiplies intonumerous copies(2).The higher expression of ACE2 in lung, heart, ileum, and kidney cells explains why these organs are affected more than others (26, 27). After intracellular replication and maturation, the host cell bursts releasing the virionsand starting a new cycle of infection(26). As cells rupture (lytic release), it is speculated that they also release intracellular components, such as extracellular cold-inducible RNA binding protein (eCIRP), double-stranded DNA, histones, and high mobility group box 1 (HMGB1)(28). Nearby cells get activated by the viral single-stranded RNA and proteins via pathogen-associated molecular pattern (PAMP) receptors, as well as by the ruptured cell contents viadamage- associated molecular pattern (DAMP) receptors(28, 29). Downstream signaling from these receptors leads to the release chemokines, antiviral cytokines, and pro-inflammatory cytokines and other mediators. As a result, patients with severe COVID-19 havea cytokine storm characterized byelevated levels of IL-2, IL-7, IL-6, tumor necrosis factor-α (TNF-α), interferon-γ Copyright © 2020 by the Shock Society. Unauthorized reproduction of this article is prohibited. inducible protein 10, monocyte chemoattractant protein-1, and macrophage inflammatory protein-1-α(4, 30).Additionally,