Sudan ebolavirus long recovered survivors produce GP-specific Abs that are of the IgG1 subclass and preferentially bind FcγRI

Radinsky, Olga; Edri, Avishay; Brusilovsky, Michael; Fedida-Metula, Shlomit; Sobarzo, Ariel; Gershoni-Yahalom, Orly; Lutwama, Julius J.; Dye, John M.; Lobel, Leslie; Porgador, Angel

doi:10.1038/s41598-017-06226-8

Cited by 12 publications

(14 citation statements)

References 41 publications

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“…In addition, the humoral response to EBOV infection was reported as absent or diminished in fatal cases, while survivors demonstrated the presence of significant levels of virus-specific IgM and IgG followed by the activation of cytotoxic cells at the time of antigen clearance from the blood [16]. Notwithstanding, the antibody response in EVD patients is still controversial and studies on this aspect are rare [17,18,19,20]; therefore, defining a comprehensive profile of the immune response is essential for the effective management of patients and countermeasure development.…”

Section: Introductionmentioning

confidence: 99%

Inflammatory and Humoral Immune Response during Ebola Virus Infection in Survivor and Fatal Cases Occurred in Sierra Leone during the 2014–2016 Outbreak in West Africa

Colavita

Biava

Castilletti

et al. 2019

Viruses

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Ebola virus (EBOV) infection is characterized by an excessive inflammatory response, a loss of lymphocytes and a general paralysis of the immune system, however pathophysiological mechanisms are not fully understood. In a cohort of 23 fatal and 21 survivors of ebola virus disease (EVD) cases admitted to the Emergency Ebola-Treatment-Center in Goderich (Freetown, Sierra Leone) during the 2014 to 2016 EBOV epidemic in Western Africa, we analyzed the pathway-focused gene expression profile of secreted proteins involved in the immune response and the levels of specific anti-EBOV IgM and IgG from the time of admission till discharge or death. We observed a dysregulated inflammatory response in fatal patients as compared to survivors, mainly consisting of the upregulation of inflammatory mediators, whose extent directly correlated with viremia levels. The upregulation persisted and intensified during the late phase of infection. Relevant differences were also found in humoral immunity, as an earlier and more robust EBOV antibody response was observed in survivor patients.

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Section: Introductionmentioning

confidence: 99%

Inflammatory and Humoral Immune Response during Ebola Virus Infection in Survivor and Fatal Cases Occurred in Sierra Leone during the 2014–2016 Outbreak in West Africa

Colavita

Biava

Castilletti

et al. 2019

Viruses

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“…Such an early stage viremia is a crucial condition for the viral infection of its arthropod vector (Hershkovitz et al, 2008). Moreover, the long-term survivors were found to mount effective antibodies specifically against the viral GP (Radinsky et al, 2017), and this was also shown in a mouse model (Ren et al, 2018). EBOV GPs were also reported recently to have additional anti-T cell activities by directly binding CD4+ T cell through interaction of GP with TLR4, resulting in significant upregulation of pathways associated with interferon signaling that leads to T cell apoptosis or necrosis (Iampietro et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

N-Glycans Mediate the Ebola Virus-GP1 Shielding of Ligands to Immune Receptors and Immune Evasion

Iraqi

Edri

Greenshpan

et al. 2020

Front. Cell. Infect. Microbiol.

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The Ebola Virus (EBOV) glycoprotein (GP) sterically shields cell-membrane ligands to immune receptors such as human leukocyte antigen class-1 (HLA-I) and MHC class I polypeptide-related sequence A (MICA), thus mediating immunity evasion. It was suggested that the abundant N-glycosylation of the EBOV-GP is involved in this steric shielding. We aimed to characterize (i) the GP N-glycosylation sites contributing to the shielding, and (ii) the effect of mutating these sites on immune subversion by the EBOV-GP. The two highly glycosylated domains of GP are the mucin-like domain (MLD) and the glycan cap domain (GCD) with three and six N-glycosylation sites, respectively. We mutated the N-glycosylation sites either in MLD or in GCD or in both domains. We showed that the glycosylation sites in both the MLD and GCD domains contribute to the steric shielding. This was shown for the steric shielding of either HLA-I or MICA. We then employed the fluorescence resonance energy transfer (FRET) method to measure the effect of N-glycosylation site removal on the distance in the cell membrane between the EBOV-GP and HLA-I (HLA.A * 0201 allele). We recorded high FRET values for the interaction of CFP-fused HLA.A * 0201 and YFP-fused EBOV-GP, demonstrating the very close distance (<10 nm) between these two proteins on the cell membrane of GP-expressing cells. The co-localization of HLA-I and Ebola GP was unaffected by the disruption of steric shielding, as the removal of N-glycosylation sites on Ebola GP revealed similar FRET values with HLA-I. However, these mutations directed to N-glycosylation sites had restored immune cell function otherwise impaired due to steric shielding over immune cell ligands by WT Ebola GP. Overall, we showed that the GP-mediated steric shielding aimed to impair immune function is facilitated by the N-glycans protruding from its MLD and GCD domains, but these N-glycans are not controlling the close distance between GP and its shielded proteins.

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“…Persistence of antigen-specific IgGs was measured by ELISA [22]. IgG functionality was measured by virus neutralization in a plaque reduction neutralization assay (PRNT) using infectious SUDV [23], and by antibody Fc-dependent reporter assay [24].…”

Section: Methodsmentioning

confidence: 99%

Multiple viral proteins and immune response pathways act to generate robust long-term immunity in Sudan virus survivors

et al. 2019

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Background Profiles of immunity developed in filovirus patients and survivors have begun to shed light on antigen-specific cellular immune responses that had been previously under-studied. However, our knowledge of the breadth and length of those responses and the viral targets which mediate long-term memory immunity still lags significantly behind. Methods We characterized antigen-specific immune responses in whole blood samples of fifteen years post-infected survivors of the Sudan virus (SUDV) outbreak in Gulu, Uganda (2000−2001). We examined T cell and IgG responses against SUDV complete antigen and four SUDV proteins; glycoprotein (GP), nucleoprotein (NP), and viral protein 30 (VP30), and 40 (VP40). Findings We found survivors-maintained antigen-specific CD4+ T cell memory immune responses mediated mainly by the viral protein NP. In contrast, activated CD8+ T cell responses were nearly absent in SUDV survivors, regardless of the stimulating antigen used. Analysis of anti-viral humoral immunity revealed antigen-specific IgG antibodies against SUDV and SUDV proteins. Survivor IgGs mediated live SUDV neutralization in vitro and FcγRI and FcγRIII antibody Fc-dependent responses, mainly via antibodies to the viral proteins GP and VP40. Interpretation We highlight the key role of several proteins, i.e., GP, NP, and VP40, to act as mediators of distinctive and sustained cellular memory immune responses in long-term SUDV survivors. We suggest that the inclusion of these viral proteins in vaccine development may best mimic survivor native memory immune responses with the potential of protecting against viral infection. Funds This research was funded by the Defense Threat Reduction Agency (CB4088) and by the National Institute Of Allergy And Infectious Diseases of the National Institutes of Health under Award Number R01AI111516. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Sudan ebolavirus long recovered survivors produce GP-specific Abs that are of the IgG1 subclass and preferentially bind FcγRI

Cited by 12 publications

References 41 publications

Inflammatory and Humoral Immune Response during Ebola Virus Infection in Survivor and Fatal Cases Occurred in Sierra Leone during the 2014–2016 Outbreak in West Africa

Inflammatory and Humoral Immune Response during Ebola Virus Infection in Survivor and Fatal Cases Occurred in Sierra Leone during the 2014–2016 Outbreak in West Africa

N-Glycans Mediate the Ebola Virus-GP1 Shielding of Ligands to Immune Receptors and Immune Evasion

Multiple viral proteins and immune response pathways act to generate robust long-term immunity in Sudan virus survivors

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