How the human immune system protects against Ebola
Two types of human antibodies that target different parts of the Ebola virus synergize their antiviral effects by inhibiting different steps of infection, according to a study published August 23 in the open-access journal PLOS Pathogens by Philipp Ilinykh and colleagues from the University of Texas Medical Branch, Vanderbilt University, and Ragon Institute. These new insights into how the human immune system protects against Ebola infections could lead to the development of effective antibody-based therapies.
The unprecedented Ebola virus epidemic in West Africa from 2013 to 2016 resulted in more than 11,000 human fatalities, demonstrating the urgent need for treatments against this virus and related highly pathogenic filoviruses. Despite intense international collaborative efforts, there is still no licensed therapeutic available against filovirus disease. Further progress in the development of effective antibody-based therapies for filovirus infections requires a better understanding of the mechanism underlying their protective effect. Although the human immune system can produce strong antibody responses against filoviruses, the effects on multiple steps of filovirus infection have not been clear.
To address this gap in knowledge, Ilinykh and colleagues evaluated the mechanisms underlying the antiviral effects of a diverse panel of monoclonal antibodies obtained from several survivors of natural Ebola virus infections. Monoclonal antibodies that targeted either the glycan cap or stem region of the viral glycoprotein interfered with and targeted different steps of filovirus infection. For example, glycan cap-specific antibodies inhibited viral attachment to the cell surface, cell-to-cell transmission and virion budding. By contrast, stem-specific antibodies triggered the activation of natural killer cells and the destruction of infected cells by monocytes and neutrophils.
Taken together, the findings suggest that different types of antibodies exert cooperative effects by blocking distinct steps of filovirus infection. According to the authors, antibody cocktails that combine complementary antiviral effects should be tested in future studies.
Bukreyev adds, "The current approach for treatment of filovirus infections with antibody cocktails tested in animal models utilizes the principle of targeting of non-overlapping epitopes. Our study suggests that possible synergistic effects of antibodies which block various steps of viral replication should be also considered."
Abstract (from POLS )
Recent studies suggest that some monoclonal antibodies (mAbs) specific for ebolavirus glycoprotein (GP) can protect experimental animals against infections. Most mAbs isolated from ebolavirus survivors appeared to target the glycan cap or the stalk region of the viral GP, which is the envelope protein and the only antigen inducing virus-neutralizing antibody response. Some of the mAbs were demonstrated to be protective in vivo. Here, a panel of mAbs from four individual survivors of ebolavirus infection that target the glycan cap or stem region were selected for investigation of the mechanisms of their antiviral effect. Comparative characterization of the inhibiting effects on multiple steps of viral replication was performed, including attachment, post-attachment, entry, binding at low pH, post-cleavage neutralization of virions, viral trafficking to endosomes, cell-to-cell transmission, viral egress, and inhibition when added early at various time points post-infection. In addition, Fc-domain related properties were characterized, including activation and degranulation of NK cells, antibody-dependent cellular phagocytosis and glycan content. The two groups of mAbs (glycan cap versus stem) demonstrated very different profiles of activities suggesting usage of mAbs with different epitope specificity could coordinate inhibition of multiple steps of filovirus infection through Fab- and Fc-mediated mechanisms, and provide a reliable therapeutic approach.
Journal Reference:
- Philipp A. Ilinykh, Rodrigo I. Santos, Bronwyn M. Gunn, Natalia A. Kuzmina, Xiaoli Shen, Kai Huang, Pavlo Gilchuk, Andrew I. Flyak, Patrick Younan, Galit Alter, James E. Crowe, Alexander Bukreyev. Asymmetric antiviral effects of ebolavirus antibodies targeting glycoprotein stem and glycan cap. PLOS Pathogens, 2018; 14 (8): e1007204 DOI: 10.1371/journal.ppat.1007204
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