Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1271456 | ENA |
REPOSITORIES: ENA
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Project description:SARS-CoV-2 has spread globally and caused the COVID-19 pandemic. Although passively delivered neutralizing antibodies against SARS-CoV-2 are in clinical trials, their mechanism of action in vivo is incompletely understood. Here, we define correlates of protection of neutralizing human monoclonal antibodies (mAbs) in SARS-CoV-2-infected mice. Whereas Fc effector functions are fully dispensable when mAbs are administered as prophylaxis, they are required for optimal protection as therapy. When given after infection, intact but not LALA-PG loss of Fc effector function variant mAbs reduce SARS-CoV-2 burden and lung disease in mice and hamsters. Fc engagement of neutralizing antibodies mitigates inflammation and improves respiratory mechanics, and transcriptional profiling suggests these phenotypes are associated with diminished innate immune signaling and enhanced tissue repair. Immune cell depletions establish that neutralizing mAbs require monocytes for therapeutic efficacy. Our study demonstrates that therapeutic neutralizing mAbs require Fc effector functions to reduce SARS-CoV-2 infection and modulate protective immune responses.
2021-03-01 | GSE161615 | GEO
Project description:Mayaro virus (MAYV) is an emerging arbovirus. Previous studies have shown antibody Fc effector functions are critical for optimal monoclonal antibody-mediated protection against alphaviruses; however, the requirement of Fc gamma receptors (FcgRs) for protection during natural infection has not been evaluated. Here, we showed mice lacking activating FcgRs (FcRg-/-) developed prolonged clinical disease with more MAYV in joint-associated tissues. Viral clearance was associated with anti-MAYV cell surface binding antibodies rather than neutralizing antibodies. Lack of Fc-FcgR engagement increased the number of monocytes through chronic timepoints. Single cell RNA sequencing showed elevated levels of pro-inflammatory monocytes in joint-associated tissue with increased MAYV RNA present in FcRg-/- monocytes and macrophages. Transfer of FcRg-/- monocytes into wild type animals was sufficient to increase virus in joint-associated tissue. Overall, this study suggests that engagement of antibody Fc with activating FcgRs promotes protective responses during MAYV infection and prevents a pro-viral role for monocytes.
2025-02-05 | GSE285678 | GEO
Project description:Respiratory syncytial virus (RSV) is a major cause of severe respiratory tract infections in infants and older adults. While vaccines have recently been approved for older adults and pregnant women, vaccine development for infants remains challenging due to the risk of vaccine-enhanced disease. Understanding immunological differences between target groups is essential for improving vaccination strategies, but no clear correlates of protection have been identified yet. Antibody Fc-mediated effector functions may play an important role. In a cohort of 24-month old children and adults (n=46 per group), we assessed RSV-specific IgG/IgA levels, IgG subclasses, avidity, Fc glycosylation, and neutralization, antibody-dependent NK cell activation (ADNKA), cellular phagocytosis (ADCP), and complement deposition (ADCD). Compared to children, antibodies from adults showed enhanced functionality. Furthermore, RSV-specific antibodies displayed differences in avidity and glycosylation patterns between the two groups, which might relate to differences in the number of previous exposures. Importantly, our data strongly suggest that IgG Fc afucosylation drives enhanced ADNKA capacity of RSV-specific antibodies. Our data provide a detailed overview of similarities and differences between the RSV-specific antibodies in children and adults. This information will support the ongoing quest for correlates of protection and the design of future vaccination strategies in different target populations.
2025-11-05 | PXD069590 | Pride
Project description:Immune responses in hemophilia A patients to replacement factor VIII can be either tolerogenic or immunogenic, the latter resulting in induction of non-neutralizing anti-factor VIII antibodies or neutralizing antibodies called inhibitors. Since these inhibitors render replacement FVIII treatment essentially ineffective, preventing or eliminating them are of top priority in disease management. The extended half-life recombinant factor VIII Fc fusion protein (rFVIIIFc) is an approved therapy for hemophilia A patients. In addition, it has been reported that rFVIIIFc can induce tolerance to FVIII in hemophilia A patients that have developed inhibitors. Given that the IgG1 Fc region has the potential to interact with immune cells expressing Fc receptors and thereby affect the immune response to rFVIII, we investigated how human macrophages, expressing both Fc receptors and receptors reported to bind FVIII, respond to rFVIIIFc. We show herein that rFVIIIFc, but not rFVIII, uniquely skews macrophages towards an alternatively activated regulatory phenotype. rFVIIIFc initiates signaling events that result in morphological changes, as well as a specific gene expression and metabolic profile that is characteristic of the regulatory type Mox/M2-like macrophages. Further, these changes are dependent on rFVIIIFc-Fc receptor interactions. Our findings elucidate mechanisms of potential immunomodulatory properties of rFVIIIFc.
2018-11-20 | GSE118157 | GEO
Project description:As the SARS-CoV-2 pandemic progressed, many monoclonal antibodies (mAbs) that neutralized infection against initial strains lost potency against later variants due to accumulation of mutations in the spike protein. Nonetheless, some mAbs, including S309, the parent of the therapeutically used sotrovimab, remained protective in animals against Omicron variants despite reduced neutralizing potential, with Fc-mediated effector functions likely sustaining inhibitory activity. Here, we identify Fc variants of S309 that confer enhanced protection against SARS-CoV-2 infection in a humanized Fcg receptor transgenic (Hu-FcgR Tg) mouse model of infection. Versions of S309 that are afucosylated (AFUC) and contain a G236A (GA) mutation in the Fc region showed increased binding to FcgRs IIA, IIIA, and IIIB and enhanced phagocytic activity in cell culture-based assays. Treatment with S309-GA-AFUC resulted in less viral burden, inflammation, and pulmonary ventilatory dysfunction in the lungs of Hu-FcgR Tg mice challenged with SARS-CoV-2 strains compared to the parental S309 mAb or a variant (S309-GRLR) lacking Fc effector functions. The enhanced protection in the lung conferred by S309-GA-AFUC required trafficking of CCR2-expressing monocytes to reduce SARS-CoV-2 viral burden and lung injury. Flow cytometry and RNA sequencing analyses showed that compared to the parental S309 mAb, S309-GA-AFUC treatment reduced the inflammatory state and induced a reparative transcriptional signature in monocytes and interstitial macrophages. Overall, our findings demonstrate that Fc engineering to increase antibody binding to activating FcgRs can strengthen effector functions, shape myeloid transcriptional profiles, and enhance protection against SARS-CoV-2 infection in vivo.
2025-12-15 | GSE313869 | GEO
Project description:Neutralizing antibodies against SARS-CoV-2 require intact Fc effector functions and monocytes for optimal therapeutic activity
| PRJNA678953 | ENA
Project description:<p>West Nile virus (WNV) infection is a mosquito-borne disease that can cause severe neurological illness. We analyzed the humoral response to WNV of subjects infected with WNV at different stages of the infection and at different levels of detail, from single cells to the repertoire level. We integrated single-cell analysis by microengraving with next-generation sequencing and identified four novel WNV neutralizing antibodies with potential use as therapeutics against WNV infection. The results indicate persistence of WNV-specific memory B cells and antibody-secreting cells in post-convalescent subjects and suggest that the antibody response itself does not predict the clinical severity of the disease. </p>
| phs001200 | dbGaP
Project description:It has been shown that antibodies can enhance Ebola virus (EBOV) infection at sub-neutralizing concentrations. The effect of antibodies on the infection of murine cell line (RAW 264.7) with MLV-EBOV, a murine leukemia virus pseudotype expressing surface glycoprotein (GP) of EBOV and green fluorescent protein (GFP) has been studied. Moreover, regions of EBOV GP targeted by antibodies enhancing the infection have been investigated. Serum and monoclonal antibodies (mAbs) were obtained from mice inoculated with MLV-EBOV. Plasma from patients and humanized anti-EBOV GP mAbs were obtained. The proportion of GFP-positive cells was determined by immunocytofluorometry. Trypsin-digested EBOV GP was incubated in affinity columns prepared with mAbs. Eluted peptides were analyzed by high-resolution mass spectrometry. The infection of cells with MLV-EBOV was enhanced by immune mouse serum, human plasma and mAbs. The infection was the result of interactions between MLV-EBOV /antibody complexes and FcγRs. Regions of EBOV GP, located in GP1 core, furin cleavage site, N-terminal part of GP2, and HR1 and HR2 domains are target of antibodies able to enhance the infection. In conclusion, the RAW 264.7 cell line associated with MLV-EBOV can be used to study the enhancing activity of murine and human antibodies and may help to select antibodies or vaccine formulations that do not lead to enhancement of EBOV infection.
2026-01-26 | PXD066513 | Pride
Project description:Messenger RNA-based vaccines against COVID-19 induce a robust anti-SARS-CoV-2 antibody response with potent viral neutralization activity. Antibody effector functions is determined by its constant region subclasses as well as by its glycosylation patterns, but their role in vaccine efficacy is not well understood. Moreover, whether vaccination induce antibodies with similar Fc structures and protection potential as in COVID-19 patients remains unclear. Here, we analyzed BNT162b2 vaccine-induced IgG subclass distribution and Fc glycosylation patterns, as well as their potential to drive effector function via Fc-gamma receptors and complement pathways. We identified a unique Fc composition of these antiviral protein antibodies that is distinct from COVID-19 patients and convalescences. Vaccine-induced anti-spike SARS-CoV-2 IgG displayed a pro-inflammatory Fc profile and superior Fab- and Fc-mediated function, as compared to antibodies generated during natural viral infection. Moreover, differences in the kinetics of IgG Fc structure formation and their engagement with immune receptors were observed between different age groups. These data highlight the heterogeneity of the IgG Fc response to SARS-CoV-2 infection and vaccination and suggest that they differently support long-lasting protection.
2021-11-29 | PXD029321 | Pride
Project description:Antibodies are key to the clearance of Bartonella bacteremia, but the mechanisms and targets of protective antibodies are unknown and bacterial evasion strategies remain elusive. We studied experimental Bartonella taylorii infection of mice, its natural host, and investigated protective immune responses. Clearance of bacteremia depended on specific antibodies that interfere with bacterial attachment to erythrocytes. Accordingly, antibodies were effective in the absence of complement and Fc-receptors. Moreover, they formed independently of B-cell hypermutation and isotype class switch. The cloning of neutralizing monoclonal antibodies (mAbs) led to the identification of the bacterial autotransporter CFA as a protective antibody target, and vaccination against CFA protected against Bartonella bacteremia. MAb binding mapped to a region of CFA that is hypervariable in both human- and mouse-pathogenic Bartonella strains, suggesting mutational antibody evasion. These insights further our understanding of Bartonella immunity and immune evasion and elucidate mechanisms driving high Bartonella prevalence in the wild.
2022-08-12 | PXD028783 | Pride