Fc gamma receptors in respiratory syncytial virus infections: implications for innate immunity

Jans, Jop; Vissers, Marloes; Heldens, Jacco; Jonge, Marien I. de; Levy, Ofer; Ferwerda, Gerben

doi:10.1002/rmv.1773

Cited by 9 publications

(7 citation statements)

References 145 publications

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“…Indeed, palivizumab (a humanized IgG antibody) and the anti‐F RS‐348 antibody (mouse IgG1 antibody) have been shown to decrease hRSV viral loads and hRSV‐associated immunopathology in mice . Nevertheless, whether virus encounter with such neutralizing antibodies can elicit enhanced antiviral T‐cell responses or protective immune memory and immunity against hRSV has not been fully evaluated . Hence, we assessed whether hRSV coated with anti‐F neutralizing antibodies could mediate virus entry into DCs or modulate their phenotype and ability to activate T cells.…”

Section: Discussionmentioning

confidence: 99%

“…Further, research is required to define whether systemic administration of this antibody can elicit protective immunity in the host during a simultaneous exposure to hRSV. A previous study suggests that palivizumab‐coated hRSV can enhance hRSV‐specific T‐cell responses during hRSV infection, whereas another proposes that antibody‐coated hRSV impair CD8 + T‐cell activation in vitro . Athough antibodies against several microbes have been shown to promote the establishment of antimicrobial T‐cell responses in animal models, the opposite has also been observed .…”

Section: Introductionmentioning

confidence: 99%

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Contribution of Fcγ receptors to human respiratory syncytial virus pathogenesis and the impairment of T‐cell activation by dendritic cells

et al. 2015

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SummaryHuman respiratory syncytial virus (hRSV) is the leading cause of infant hospitalization related to respiratory disease. Infection with hRSV produces abundant infiltration of immune cells into the airways, which combined with an exacerbated pro-inflammatory immune response can lead to significant damage to the lungs. Human RSV re-infection is extremely frequent, suggesting that this virus may have evolved molecular mechanisms that interfere with host adaptive immunity. Infection with hRSV can be reduced by administering a humanized neutralizing antibody against the virus fusion protein in high-risk infants. Although neutralizing antibodies against hRSV effectively block the infection of airway epithelial cells, here we show that both, bone marrow-derived dendritic cells (DCs) and lung DCs undergo infection with IgG-coated virus (hRSV-IC), albeit abortive. Yet, this is enough to negatively modulate DC function. We observed that such a process is mediated by Fcc receptors (FccRs) expressed on the surface of DCs. Remarkably, we also observed that in the absence of hRSV-specific antibodies FccRIII knockout mice displayed significantly less cellular infiltration in the lungs after hRSV infection, compared with wild-type mice, suggesting a potentially harmful, IgG-independent role for this receptor in hRSV disease. Our findings support the notion that FccRs can contribute significantly to the modulation of DC function by hRSV and hRSV-IC. Further, we provide evidence for an involvement of FccRIII in the development of hRSV pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Contribution of Fcγ receptors to human respiratory syncytial virus pathogenesis and the impairment of T‐cell activation by dendritic cells

et al. 2015

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“…These effector functions include antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP) and complement-dependent cytotoxicity (CDC); mechanisms that can eliminate infected cells or virions [60]. The importance of these effector functions is increasingly recognized for antibody mediated protection against infections with e.g., influenza virus, RSV, Zika virus and HIV [61,62,63,64,65,66,67]. VHHs lack the Fc region and therefore cannot facilitate such effector functions as such.…”

Section: Arming Vhhs With Effector Functionsmentioning

confidence: 99%

Single-Domain Antibodies and Their Formatting to Combat Viral Infections

et al. 2018

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Since their discovery in the 1990s, single-domain antibodies (VHHs), also known as Nanobodies®, have changed the landscape of affinity reagents. The outstanding solubility, stability, and specificity of VHHs, as well as their small size, ease of production and formatting flexibility favor VHHs over conventional antibody formats for many applications. The exceptional ease by which it is possible to fuse VHHs with different molecular modules has been particularly explored in the context of viral infections. In this review, we focus on VHH formats that have been developed to combat viruses including influenza viruses, human immunodeficiency virus-1 (HIV-1), and human respiratory syncytial virus (RSV). Such formats may significantly increase the affinity, half-life, breadth of protection of an antiviral VHH and reduce the risk of viral escape. In addition, VHHs can be equipped with effector functions, for example to guide components of the immune system with high precision to sites of viral infection.

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“…We did not see a correlation between ADE in vitro and disease severity for the infants in our cohort with the assays described in this paper. However, multiple additional antibody functions that may have immunomodulatory effects have not been tested yet (reviewed in reference 48 ). In addition, using THP-1 cells as a model system only demonstrates the effect on monocytes, whereas other immune cells express different combinations of FCGRs and could react differently.…”

Section: Discussionmentioning

confidence: 99%

In Vitro Enhancement of Respiratory Syncytial Virus Infection by Maternal Antibodies Does Not Explain Disease Severity in Infants

Erp

Kasteren

Guichelaar

et al. 2017

J Virol

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Respiratory syncytial virus (RSV) is the leading cause of severe respiratory illness in infants. At this young age, infants typically depend on maternally transferred antibodies (matAbs) and their innate immune system for protection against infections. RSV-specific matAbs are thought to protect from severe illness, yet severe RSV disease occurs mainly below 6 months of age, when neutralizing matAb levels are present. To investigate this discrepancy, we asked if disease severity is related to antibody properties other than neutralization. Some antibody effector functions are mediated via their Fc binding region. However, it has been shown that this binding may lead to antibody-dependent enhancement (ADE) of infection or reduction of neutralization, both possibly leading to more disease. In this study, we first showed that high levels of ADE of RSV infection occur in monocytic THP-1 cells in the presence of RSV antibodies and that neutralization by these antibodies was reduced in Vero cells when they were transduced with Fc gamma receptors. We then demonstrated that antibodies from cotton rats with formalin-inactivated (FI)-RSV-induced pulmonary pathology were capable of causing ADE. Human matAbs also caused ADE and were less neutralizing in vitro in cells that carry Fc receptors. However, these effects were unrelated to disease severity because they were seen both in uninfected controls and in infants hospitalized with different levels of RSV disease severity. We conclude that ADE and reduction of neutralization are unlikely to be involved in RSV disease in infants with neutralizing matAbs.IMPORTANCE It is unclear why severity of RSV disease peaks at the age when infants have neutralizing levels of maternal antibodies. Additionally, the exact reason for FI-RSV-induced enhanced disease, as seen in the 1960s vaccine trials, is still unclear. We hypothesized that antibodies present under either of these conditions could contribute to disease severity. Antibodies can have effects that may lead to more disease instead of protection. We investigated two of those effects: antibody-dependent enhancement of infection (ADE) and neutralization reduction. We show that ADE occurs in vitro with antibodies from FI-RSV-immunized RSV-infected cotton rats. Moreover, passively acquired maternal antibodies from infants had the capacity to induce ADE and reduction of neutralization. However, no clear association with disease severity was seen, ruling out that these properties explain disease in the presence of maternal antibodies. Our data contribute to a better understanding of the impact of antibodies on RSV disease in infants.

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Fc gamma receptors in respiratory syncytial virus infections: implications for innate immunity

Cited by 9 publications

References 145 publications

Contribution of Fcγ receptors to human respiratory syncytial virus pathogenesis and the impairment of T‐cell activation by dendritic cells

Contribution of Fcγ receptors to human respiratory syncytial virus pathogenesis and the impairment of T‐cell activation by dendritic cells

Single-Domain Antibodies and Their Formatting to Combat Viral Infections

In Vitro Enhancement of Respiratory Syncytial Virus Infection by Maternal Antibodies Does Not Explain Disease Severity in Infants

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