FcγR-mediated SARS-CoV-2 infection of monocytes activates inflammation

Junqueira, Caroline; Crespo, Ângela C.; Ranjbar, Shahin; Lacerda, Luna Barrôco de; Lewandrowski, Mercedes; Ingber, Jacob; Parry, Blair A.; Ravid, Sagi; Clark, Sarah A.; Schrimpf, Marie Rose; Ho, Felicia; Beakes, Caroline; Margolin, Justin D.; Russell, Nicole; Kays, Kyle R.; Boucau, Julie; Adhikari, Upasana Das; Vora, Setu M.; Leger, Valerie; Gehrke, Lee; Henderson, Lauren A.; Janssen, Erin; Kwon, Douglas S.; Sander, Chris; Abraham, Jonathan; Goldberg, Marcia B.; Wu, Hao; Mehta, Gautam; Bell, Steven; Goldfeld, Anne E.; Filbin, Michael R.; Lieberman, Judy

doi:10.1038/s41586-022-04702-4

Cited by 352 publications

(345 citation statements)

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“… 50 − 52 Interestingly, a very recent report demonstrated antibody-dependent uptake of SARS-CoV-2 by circulating monocytes via Fcγ receptors. 53 Another option could be the donor-specific protein corona composition that might contain immune uptake-inhibiting factors (called dysopsonins 54 ).…”

Section: Discussionmentioning

confidence: 99%

Antibody-Dependent Complement Responses toward SARS-CoV-2 Receptor-Binding Domain Immobilized on “Pseudovirus-like” Nanoparticles

Gaikwad

Wang

et al. 2022

ACS Nano

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Many aspects of innate immune responses to SARS viruses remain unclear. Of particular interest is the role of emerging neutralizing antibodies against the receptor-binding domain (RBD) of SARS-CoV-2 in complement activation and opsonization. To overcome challenges with purified virions, here we introduce “pseudovirus-like” nanoparticles with ∼70 copies of functional recombinant RBD to map complement responses. Nanoparticles fix complement in an RBD-dependent manner in sera of all vaccinated, convalescent, and naïve donors, but vaccinated and convalescent donors with the highest levels of anti-RBD antibodies show significantly higher IgG binding and higher deposition of the third complement protein (C3). The opsonization via anti-RBD antibodies is not an efficient process: on average, each bound antibody promotes binding of less than one C3 molecule. C3 deposition is exclusively through the alternative pathway. C3 molecules bind to protein deposits, but not IgG, on the nanoparticle surface. Lastly, “pseudovirus-like” nanoparticles promote complement-dependent uptake by granulocytes and monocytes in the blood of vaccinated donors with high anti-RBD titers. Using nanoparticles displaying SARS-CoV-2 proteins, we demonstrate subject-dependent differences in complement opsonization and immune recognition.

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Section: Discussionmentioning

confidence: 99%

Antibody-Dependent Complement Responses toward SARS-CoV-2 Receptor-Binding Domain Immobilized on “Pseudovirus-like” Nanoparticles

Gaikwad

Wang

et al. 2022

ACS Nano

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“…In a recent study, Junqueira et al isolated mononuclear cells from COVID-19 patients and found that only monocytes expressing FcγRIIIa (CD16) – a key receptor for antibody-dependent Fc-mediated phagocytosis – stained positive for SARS-CoV-2 nucleocapsid (N) protein, indicating virus internalization [ 5 ]. Furthermore, ~95% of COVID-19 N + monocytes stained positive for J2 [an antibody to double-stranded (ds)RNA], indicating active infection.…”

mentioning

confidence: 99%

“…On the other hand, IgG- but not IgA-depleted COVID-19 plasma abrogated viral infection, suggesting that SARS-CoV-2-specific IgG antibodies could be key to infecting CD16 + monocytes ( Figure 1 ). SARS-CoV-2 infection of monocytes was not prevented by camostat mesylate (an inhibitor of the spike protein priming protease TMPRSS2) or by blocking antibodies against the SARS-CoV-2 receptor ACE2 [ 6 ], suggesting an ACE-2 independent route of entry [ 5 ]. Instead, blocking antibodies against the Fc receptors CD16 (FcγRIIIa) and CD64 (FcγRI), but not CD32 (FcγRIIa), were effective in inhibiting SARS-CoV-2 infection of monocytes, highlighting possible entry routes for antibody-opsonized virus.…”

mentioning

confidence: 99%

“…This causes the infected monocytes to undergo pyroptosis and rupture instead, releasing mature, active proinflammatory cytokines such as IL-18 and IL-1β into the milieu ⑧. This in turn could recruit more immune cells to the site, perpetuating the inflammatory cascade and leading to a cytokine storm [ 5 ]. Steps which remain unclear after the current study [ 5 ] and warrant further research are indicated in red.…”

mentioning

confidence: 99%

“…This in turn could recruit more immune cells to the site, perpetuating the inflammatory cascade and leading to a cytokine storm [ 5 ]. Steps which remain unclear after the current study [ 5 ] and warrant further research are indicated in red. Abbreviation: SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.…”

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confidence: 99%

See 2 more Smart Citations

Insights into how SARS-CoV2 infection induces cytokine storms

Selva

Chung

2022

Trends in Immunology

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Inducing Long Lasting B Cell and T Cell Immunity Against Multiple Variants of SARS‐CoV‐2 Through Mutant Bacteriophage Qβ—Receptor Binding Domain Conjugate

Tan,

Yang,

Lin

et al. 2024

Adv Healthcare Materials

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More than three years into the global pandemic, SARS‐CoV‐2 remains a significant threat to public health. Immunities acquired from infection or current vaccines fail to provide long term protection against subsequent infections, mainly due to their fast‐waning nature and the emergence of variants of concerns (VOCs) such as Omicron. To overcome these limitations, SARS‐CoV‐2 Spike protein receptor binding domain (RBD)‐based epitopes were investigated as conjugates with a powerful carrier, the mutant bacteriophage Qβ (mQβ). The epitope design was critical to eliciting potent antibody responses with the full length RBD being superior to peptide and glycopeptide antigens. The full length RBD conjugated with mQβ activated both humoral and cellular immune systems in vivo, inducing broad spectrum, persistent and comprehensive immune responses effective against multiple VOCs including Delta and Omicron variants, rendering it a promising vaccine candidate.This article is protected by copyright. All rights reserved

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FcγR-mediated SARS-CoV-2 infection of monocytes activates inflammation

Cited by 352 publications

References 54 publications

Antibody-Dependent Complement Responses toward SARS-CoV-2 Receptor-Binding Domain Immobilized on “Pseudovirus-like” Nanoparticles

Antibody-Dependent Complement Responses toward SARS-CoV-2 Receptor-Binding Domain Immobilized on “Pseudovirus-like” Nanoparticles

Insights into how SARS-CoV2 infection induces cytokine storms

Inducing Long Lasting B Cell and T Cell Immunity Against Multiple Variants of SARS‐CoV‐2 Through Mutant Bacteriophage Qβ—Receptor Binding Domain Conjugate

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