key: cord-0957438-tyhy784d
authors: Gómez-Rial, J.; Martinón-Torres, F.
title: A strategy targeting monocyte-macrophage differentiation to avoid pulmonary complications in SARS-Cov2 infection
date: 2020-04-23
journal: Clin Immunol
DOI: 10.1016/j.clim.2020.108442
sha: 629ade258cb83b71ccaf5afd9dd4c6cfae1dd005
doc_id: 957438
cord_uid: tyhy784d

nan

Authors:

Gómez-Rial J, MD 1,2 , Martinón-Torres F, MD, Phd, Assoc Prof 1 The immune dysregulation and cytokine storm observed in severe COVID-19 cases has led to the trial of licensed RA drugs such as Chloroquine, IL-1/IL-6 blockers, TNF or Janus kinase inhibitors in COVID-19 patients [1] In addition we propose that blockade of granulocyte macrophage-colony stimulating factor (GM-CSF) may be an effective strategy to prevent pulmonary complications and fatality in SARS-Cov2 infection.

Clinical findings in severe COVID-19 cases indicate a dysregulated innate immune response with an overexuberant inflammation, characterized by a cytokine storm syndrome that is responsible for the associated respiratory failure, multiorgan failure and lethality. Analysis of cytokine profiles in COVID-19 patients shows some similarities to secondary haemophagocytic syndrome (sHPS), with increased IL-2, IL-6, IL-7, GM-CSF, IP-10, MCP-1, MIP-1 and TNF- [2] . In this uncommon and potentially fatal disorder, severe hyperinflammation is caused by uncontrolled proliferation and activation of macrophages, which secrete high amounts of inflammatory cytokines and show increased phagocytic activity [3] . Causes for this pathological immune activation can be genetic or secondary under sporadic conditions such as viral infection. This virus-associated hemophagocytic syndrome (VAHS) has been extensively studied, with severe complications often resulting in multiorgan failure and death. During several influenza pandemics such as 2009 influenza A H1N1, 1918 H1N1 and 1998 H5N1, VAHS was shown to represent an important contributor to associated respiratory failure and high lethality rates [4, 5] . Findings from these cases showed involvement of a massive macrophage activation and rapid occurrence of multi-organ failure.

and inflammation-related phenotypic changes in peripheral blood monocytes, and correlation with acute respiratory distress syndrome (ARDS) in severe patients [5] Furthermore, single-cell RNA sequencing of lung bronchoalveolar immune cells infection [6] If these findings are confirmed, they would indicate that in SARS-Cov2, similarly to SARS-Cov1, acute lethal disease is produced by delayed and dysregulated type I interferon response and pulmonary accumulation of inflammatory monocytemacrophages, which are mainly responsible for immunopathology [6, 7] . This would identify these cells as potential therapeutic targets in severe patients. Furthermore, SARS-Cov1 has demonstrated ability to infect primary human monocyte-derived macrophages in vitro; antibody-dependent enhancement (ADE) of macrophages by non-neutralizing antiviral antibodies has been shown during other coronavirus infections [8] , skewing macrophages to a hyper-activated pathogenic response.

During infection and inflammatory response, bloodstream monocytes derived from precursors in the bone marrow are recruited and stimulated to differentiate into macrophage cell population. This recruitment is essential for an effective control and clearance of viral infection, but it also contributes to the pathogenesis and degenerative disease in an uncontrolled immune response [9] . GM-CSF is the main cytokine implicated in recruitment, activation and monocyte-macrophage differentiation [10] ; several pre-clinical models and clinical trials have demonstrated that harmful over-inflammation can be controlled by targeting the action of this cytokine [11] .

Preliminary results indicate that therapeutic blockade of interleukin-6 (IL-6), another macrophage related-cytokine involved in RA pathogenesis, is also effective in severe COVID-19 patients [12] . IL-6 is a potent pro-inflammatory cytokine mainly produced by Otilimab has shown promising results during initial developmental phases and might constitute a good therapeutic candidate in COVID-19, alone or in combination with other immunosuppressive drugs such as IL-6 blockaders and anti-viral regimes. Given the circumstances, these drugs might be also considered in COVID-19 patients therapy, leveraging their application on the limited but already available safety profile from their use in the performed and ongoing clinical trials.

The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): The Perspectives of clinical immunologists from China

COVID-19: consider cytokine storm syndromes and immunosuppression

How I treat hemophagocytic lymphohistiocytosis

Virus-associated hemophagocytic syndrome as a major contributor to death in patients with 2009 influenza A (H1N1) infection. Crit Care

Influenza pandemics: past, present and future

Dysregulated Type I Interferon and Inflammatory Monocyte-Macrophage Responses Cause Lethal Pneumonia in SARS-CoV-Infected Mice

Cytokine responses in severe acute respiratory syndrome coronavirus-infected macrophages in vitro: possible relevance to pathogenesis

Anti-spike IgG causes severe acute lung injury by skewing macrophage responses during acute SARS-CoV infection

Monocyte recruitment during infection and inflammation

Defining GM-CSF-and macrophage-CSF-dependent macrophage responses by in vitro models

GM-CSF-Dependent Inflammatory Pathways. Front Immunol

The cytokine release syndrome (CRS) of severe COVID-19 and Interleukin-6 receptor (IL-6R) antagonist Tocilizumab may be the key to reduce the mortality