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Fc-optimized antibodies elicit CD8 immunity to viral respiratory infection.

ABSTRACT: Antibodies against viral pathogens represent promising therapeutic agents for the control of infection, and their antiviral efficacy has been shown to require the coordinated function of both the Fab and Fc domains¹. The Fc domain engages a wide spectrum of receptors on discrete cells of the immune system to trigger the clearance of viruses and subsequent killing of infected cells^1-4. Here we report that Fc engineering of anti-influenza IgG monoclonal antibodies for selective binding to the activating Fcγ receptor FcγRIIa results in enhanced ability to prevent or treat lethal viral respiratory infection in mice, with increased maturation of dendritic cells and the induction of protective CD8⁺ T cell responses. These findings highlight the capacity for IgG antibodies to induce protective adaptive immunity to viral infection when they selectively activate a dendritic cell and T cell pathway, with important implications for the development of therapeutic antibodies with improved antiviral efficacy against viral respiratory pathogens.

SUBMITTER: Bournazos S

PROVIDER: S-EPMC7672690 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Fc-optimized antibodies elicit CD8 immunity to viral respiratory infection.

Bournazos Stylianos S Corti Davide D Virgin Herbert W HW Ravetch Jeffrey V JV

Nature 20201008 7838

Antibodies against viral pathogens represent promising therapeutic agents for the control of infection, and their antiviral efficacy has been shown to require the coordinated function of both the Fab and Fc domains<sup>1</sup>. The Fc domain engages a wide spectrum of receptors on discrete cells of the immune system to trigger the clearance of viruses and subsequent killing of infected cells<sup>1-4</sup>. Here we report that Fc engineering of anti-influenza IgG monoclonal antibodies for selecti ...[more]

PMID: 33032297

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Project description:IntroductionEpidemiological evidences reveal that populations with psychological stress have an increased likelihood of respiratory viral infection involving influenza A virus (IAV) and SARS-CoV-2.ObjectivesThis study aims to explore the potential correlation between psychological stress and increased susceptibility to respiratory viral infections and how this may contribute to a more severe disease progression.MethodsA chronic restraint stress (CRS) mouse model was used to infect IAV and estimate lung inflammation. Alveolar macrophages (AMs) were observed in the numbers, function and metabolic-epigenetic properties. To confirm the central importance of the gut microbiome in stress-exacerbated viral pneumonia, mice were conducted through microbiome depletion and gut microbiome transplantation.ResultsStress exposure induced a decline in Lactobacillaceae abundance and hence γ-aminobutyric acid (GABA) level in mice. Microbial-derived GABA was released in the peripheral and sensed by AMs via GABAAR, leading to enhanced mitochondrial metabolism and α-ketoglutarate (αKG) generation. The metabolic intermediator in turn served as the cofactor for the epigenetic regulator Tet2 to catalyze DNA hydroxymethylation and promoted the PPARγ-centered gene program underpinning survival, self-renewing, and immunoregulation of AMs. Thus, we uncover an unappreciated GABA/Tet2/PPARγ regulatory circuitry initiated by the gut microbiome to instruct distant immune cells through a metabolic-epigenetic program. Accordingly, reconstitution with GABA-producing probiotics, adoptive transferring of GABA-conditioned AMs, or resumption of pulmonary αKG level remarkably improved AMs homeostasis and alleviated severe pneumonia in stressed mice.ConclusionTogether, our study identifies microbiome-derived tonic signaling tuned by psychological stress to imprint resident immune cells and defensive response in the lungs. Further studies are warranted to translate these findings, basically from murine models, into the individuals with psychiatric stress during respiratory viral infection.

Dataset Information

Fc-optimized antibodies elicit CD8 immunity to viral respiratory infection.

Publications

Fc-optimized antibodies elicit CD8 immunity to viral respiratory infection.

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