Severe Clinical Worsening in COVID-19 and Potential Mechanisms of Immune-Enhanced Disease.

John P Hussman

doi:10.3389/fmed.2021.637642

Abstract

Infection by the novel SARS-CoV-2 coronavirus produces a range of 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. Although 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. Dysregulated immune responses could then contribute to disease severity. This article discusses the potential role of monocyte/macrophage (Mo/Mϕ) 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 (FcγR)-expressing immune cells, and induction of autoantibodies with cross-reactivity against host proteins. While the potential roles of Mo/Mϕ 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 therapeutic candidates targeting the dysregulated immune response.

Highlights

The SARS-CoV-2 coronavirus emerged in late-2019 in Wuhan, China, presenting as pneumonia of unknown etiology
The outcomes of SARS-CoV-2 infection can range from asymptomatic presentation to critical respiratory failure, tissue damage, organ failure, and fatality
It is possible that this shift toward poor clinical outcomes corresponds to a change in viral tropism from infection of cells comprising respiratory linings and alveolar epithelia to direct viral infection of immune cells such as monocytes and alveolar macrophages

Summary

INTRODUCTION

The SARS-CoV-2 coronavirus emerged in late-2019 in Wuhan, China, presenting as pneumonia of unknown etiology. In human patients with SARS-CoV infection, increased CXCL10/IP-10 levels in immune cells and lung epithelia are induced in an IFN-independent manner, and correlate with recruitment of CD68+ monocytes into interstitial lung tissue, accompanied by progressive lymphopenia and elevated LDH, consistent with rapid recruitment and apoptosis of T-lymphocytes [26]. Cross-linking of FcγRs by IgG ICs induces macrophage activation and a switch in metabolic programming to glycolysis, accompanied by hypoxia-inducible factor HIF-1α dependent cytokine release, mirroring outcomes observed in IC-mediated autoinflammatory disease [73] In this context, it is notable that monocytes from patients with severe COVID-19 show high expression of HIF-1α and associated target genes, compared with healthy controls. Following viral infection of immune cells, viral components such as glycosylated membrane proteins activate signaling by innate pattern recognition receptors, resulting in downstream transcription that may include dysregulated production of inflammatory cytokines and chemokines. DENV infection in monocytes is detected by TLR2/6, with CD14 acting as a co-receptor, resulting in the induction of pro-inflammatory cytokine expression via NF-κB signaling pathway [86]

DISCUSSION AND IMPLICATIONS

Findings

DATA AVAILABILITY STATEMENT