Mo/M? have high phagocytic activity, and provide an early line of immune surveillance and defense by ingesting and degrading viruses, releasing cytokines in response to PRR signaling, and bridging the innate and adaptive immune system as professional antigen-presenting cells. responses could then contribute to disease severity. This article discusses the potential role of monocyte/macrophage (Mo/M?) infection by SARS-CoV-2 in mediating the immune response in severe COVID-19. Additional mechanisms of immune-enhanced disease, comprising maladaptive immune responses that may aggravate rather than alleviate severity, are also discussed. Severe acute clinical worsening in COVID-19 patients may be influenced by the emergence of antibodies that participate in hyperinflammatory monocyte response, release of neutrophil extracellular traps (NETs), thrombosis, platelet apoptosis, viral entry into Fc gamma receptor (FcR)-expressing immune cells, and induction of autoantibodies with cross-reactivity against host proteins. While the potential roles of Mo/M? infection and immune-enhanced pathology in COVID-19 are consistent with a broad range of clinical and laboratory findings, their prominence remains tentative pending further validation. In the interim, these proposed mechanisms present immediate avenues of inquiry that may help to evaluate the safety of candidate vaccines and antibody-based therapeutics, and to support consideration of pathway-informed, well-tolerated Escitalopram therapeutic candidates targeting the dysregulated immune response. Keywords: COVID-19, clinical deterioration, Escitalopram monocytes/macrophages, antibodies, vaccines Introduction The SARS-CoV-2 coronavirus emerged in late-2019 in Wuhan, China, presenting as pneumonia of unknown etiology. The virus was isolated on January 7, 2020, and its genetic sequence was published 5 days later. Within 10 weeks, the associated disease, COVID-19, was declared a global pandemic by the World Health Organization (WHO). As of December 2020, 65 million confirmed or probable cases of SARS-CoV-2 infection have been identified, with over 1.5 million fatalities (1). Severe clinical outcomes and fatalities among a subset of symptomatic COVID-19 patients have created an urgent need for the development of safe and effective vaccines and therapeutics. Infection by the novel SARS-CoV-2 coronavirus results in multi-modal outcomes, with the majority of cases producing mild or asymptomatic effects, and a smaller subset progressing to critical or fatal COVID-19 disease featuring severe acute respiratory distress. While the mechanisms driving severe disease progression remain unknown, it is possible that the abrupt clinical deterioration observed in patients with critical disease corresponds to a discrete underlying expansion of viral tropism, from infection of cells comprising respiratory linings and alveolar epithelia to direct infection and activation of inflammatory monocytes and macrophages. Direct viral infection Itga2b of these cells can promote a transcriptional shift toward invasive and inflammatory phenotypes, consistent with those observed in severe COVID-19. This shift may coincide with the induction of antibodies that participate in immune-enhanced disease severity. We begin by describing several immune hallmarks of mild vs. severe COVID-19, with an emphasis on the contribution of inflammatory monocyte/macrophage (Mo/M?) subsets to features observed in patients with severe disease. Potential mechanisms of Mo/M? infection and immune-enhanced disease progression are discussed. Immune enhancement in this context refers to maladaptive immune responses that may aggravate rather than alleviate disease severity, beyond cytopathic effects of the virus. Attention is given to the emergence of neutralizing IgG antibodies directed against the SARS-CoV-2 spike, and their potential contribution to hyperinflammatory monocyte response, release of neutrophil extracellular traps (NETs), thrombosis, platelet apoptosis, and antibody-dependent enhancement (ADE) of viral entry into Fc gamma receptor (FcR)-expressing immune cells. Features of antibody response that may be relevant in the evaluation of vaccine safety are described, including IgG fucosylation, potential generation of autoantibodies with cross-reactivity to host proteins, and interactions of antigenCantibody immune-complexes with Fc receptors and components of the complement pathway. Signal transduction pathways, particularly downstream of viral pattern-recognition receptors (PRRs) and FcRs, are also discussed in the context of immune-enhanced pathology and possible therapeutic modulation. The potential roles of monocyte/macrophage infection and immune-enhanced pathology in COVID-19 are consistent with a broad range of evidence, but their prominence remains tentative pending further validation. In the interim, these proposed mechanisms present specific points of investigation that may be of immediate benefit Escitalopram in the testing of candidate biological interventions. The development of Escitalopram safe and effective vaccines and antibody-based therapeutics relies on evaluation to limit the possibility of immune-enhanced disease. Clinical treatment of active cases may also benefit from the consideration of pathway-informed, well-tolerated therapeutic candidates targeting mediators of the maladaptive immune response. Immune Correlates of Disease Progression in Covid-19 Immune defense against viral pathogens involves the coordination of immediate innate and later pathogen-specific adaptive responses that promote viral recognition, containment, clearance, and host immunological memory. Entry of enveloped viruses such as coronaviruses into host target cells is achieved by binding of a viral surface protein to a receptor protein on the host cell membrane, followed by membrane fusion or endocytosis, and introduction of the viral genome into the host cell. Viral components and genetic material are sensed by Escitalopram host innate PRRs such as Toll-like (TLR), NOD-like (NLR), C-type lectin (CLR),.