COVID-19 and HIV-Associated Immune Reconstitution Inflammatory Syndrome: Emergence of Pathogen-Specific Immune Responses Adding Fuel to the Fire.

Nabila Seddiki,Martyn French

doi:10.3389/fimmu.2021.649567

Abstract

Both coronavirus disease 2019 (COVID-19) and mycobacterial immune reconstitution inflammatory syndrome (IRIS) in patients with HIV-1 infection result from immunopathology that is characterized by increased production of multiple pro-inflammatory chemokines and cytokines associated with activation of myeloid cells (monocytes, macrophages and neutrophils). We propose that both conditions arise because innate immune responses generated in the absence of effective adaptive immune responses lead to monocyte/macrophage activation that is amplified by the emergence of a pathogen-specific adaptive immune response skewed towards monocyte/macrophage activating activity by the immunomodulatory effects of cytokines produced during the innate response, particularly interleukin-18. In mycobacterial IRIS, that disease-enhancing immune response is dominated by a Th1 CD4+ T cell response against mycobacterial antigens. By analogy, it is proposed that in severe COVID-19, amplification of monocyte/macrophage activation results from the effects of a SARS-CoV-2 spike protein antibody response with pro-inflammatory characteristics, including high proportions of IgG3 and IgA2 antibodies and afucosylation of IgG1 antibodies, that arises from B cell differentiation in an extra-follicular pathway promoted by activation of mucosa-associated invariant T cells. We suggest that therapy for the hyperinflammation underlying both COVID-19 and mycobacterial IRIS might be improved by targeting the immunomodulatory as well as the pro-inflammatory effects of the ‘cytokine storm’.

Highlights

Infection with the novel coronavirus SARS-CoV-2 has very variable outcomes ranging from an asymptomatic infection through to coronavirus disease 2019 (COVID-19), which usually presents as respiratory tract disease ranging in severity from a flu-like illness to a severe viral pneumonia that may progress to acute respiratory distress syndrome (ARDS) and/or critical illness in about 20% of patients [1, 2]
The original contributions presented in the study are included in the article/supplementary material
Further inquiries can be directed to the corresponding author

Summary

INTRODUCTION

Infection with the novel coronavirus SARS-CoV-2 has very variable outcomes ranging from an asymptomatic infection through to coronavirus disease 2019 (COVID-19), which usually presents as respiratory tract disease ranging in severity from a flu-like illness to a severe viral pneumonia that may progress to acute respiratory distress syndrome (ARDS) and/or critical illness in about 20% of patients [1, 2]. In a very comprehensive analysis of antibody responses against SARS-CoV-2 undertaken by Zohar et al [51], it was observed that patients with severe COVID-19 (requiring admission to an intensive care unit), when compared to patients with moderate COVID-19, possessed IgG antibodies at 2 weeks after presentation that exhibited functional characteristics likely to induce monocyte/macrophage activation Those characteristics included higher serum levels of antibodies to the SARS-CoV-2 SP, including the receptor binding domain (RBD), belonging to the IgG3 subclass, the most pro-inflammatory IgG subclass [52], greater antibody binding to FcgRIIa, FcgRIIb, FcgRIIIa and FcgRIIIb, and greater antibody-dependent phagocytosis and NK cell activating activity. Investigating the effects of inhibiting IL-18 activity with humanized monoclonal antibodies to IL-18 [82], or suppression of NLRP3-inflammasome activation, is supported by preliminary data from uncontrolled, but more than one, clinical studies in patients with COVID-19 reporting a beneficial effect of inhibiting NLRP3inflammasome activity with colchicine [83, 84]

SUMMARY AND CONCLUSIONS

Findings

DATA AVAILABILITY STATEMENT