Aayushi Gaur, University Institute of Engineering and Technology, Kurukshetra University
Antiviral antibodies, in general, are considered antiviral because they play an important role in the control of virus infections in a variety of ways. But the presence of these antibodies might be advantageous to the virus in some cases. Antibody-dependent enhancement (ADE) of viral infections is the term used in those cases.
ADE
Antibody-dependent enhancement (ADE) is the process in which virus-specific antibodies interact with Fcγ (fragment crystallizable) and/or similar receptors to facilitate replication into monocytes/macrophages and granulocytic cells in certain circumstances. But in most cases, it enhances the chances of virus entry. This behavior has been observed in in-vitro and in vivo in viruses belonging to diverse families and genera.
Antigenic diversity, preferential replication in macrophages, and the potential to develop persistence are some of the characteristics shared by all the viruses across multiple categories.
Causes of ADE
ADE is predominantly a result of the antibody’s non-neutralizing character (binding to viral epitopes other than those important in cell attachment and entry) or the existence of antibodies at sub-neutralizing concentrations (binding to viral epitopes below the threshold for neutralization). Antibodies facilitate virus entrance into target cells in either case, resulting in enhanced viral infection, and this phenomenon is known as an antibody-dependent enhancement.
Internalization of virus–antibody immune complexes into cells is mediated by the interaction of the antibody Fc region with cellular Fc receptors (FcRs). As a result, FcR-positive myeloid cells such as monocytes, macrophages, dendritic cells, and certain granulocytes are permissive to ADE infection via phagocytic absorption of immune complexes. IgG antibodies are largely responsible for ADE. However, IgM antibodies in combination with complementary systems and IgA antibodies were also found to cause ADE.
Initially, it was thought that antibody’s involvement in increasing viral infection was confined to facilitating virus entrance into host cells, leading to a rise in the number of infected cells and, as a result, increased virus production, in a process known as “extrinsic ADE.”
Internalized immune complexes, on the other hand, appear to increase viral replication by suppressing cellular innate antiviral immune responses, according to research on the Ross River Virus. This process is known as “intrinsic ADE,” and it has also been found in flaviviruses. Hence, ADE is considered to be a complex process with both extrinsic and intrinsic components that work together to increase viral infection and reproduction. The enormous release of inflammatory and vasoactive mediators by host cells as a result of increased virus production leads to an aggravation of viral pathogenesis and illness severity.
Is ADE the result of a disease?
Most illnesses do not cause ADE, however, the dengue virus is one of the well-studied pathogens that may induce ADE. Dengue fever is one of the most prevalent diseases in the world, affecting hundreds of millions of people each year and killing tens of thousands. Unlike viruses like those causing measles or mumps, which have only one kind, the dengue virus has four types or serotypes. Although these serotypes are quite similar, little variations between them set the scene for ADE. When a person is infected with one serotype of the dengue virus, they usually experience minor symptoms and develop a protective immune response against that serotype, including neutralizing antibodies.
However, if that individual contracts a second serotype of dengue virus, the neutralizing antibodies produced during the first infection may attach to the virus and boost the virus’s capacity to penetrate cells, leading to ADE and a severe version of the disease known as dengue hemorrhagic fever.
The vaccine in connection with ADE
Vaccination has resulted in ADE on a few occasions:
- RSV (Respiratory syncytial virus) – RSV is a virus that causes pneumonia in youngsters often. RSV was grown, purified, and inactivated with the chemical formaldehyde to create a vaccine. Children who received the vaccination were more likely to develop or die from pneumonia after contracting RSV in clinical trials. The vaccination studies were halted as a result of this discovery, and the vaccine was never approved or released to the public.
- Measles — Formaldehyde was used to inactivate the measles virus in an early version of the measles vaccination. Children who had been vaccinated but later had measles in the community suffered high fevers, an uncommon rash, and an unusual kind of pneumonia. The vaccine was withdrawn from use when these findings were discovered, and people who had received this form of the vaccine were advised to get vaccinated again with the live, weakened measles vaccine, which does not induce ADE and is still in use today.
- Dengue virus vaccine — In 2016, a vaccine against all four serotypes of the virus was developed. The aim was that by eliciting immune responses to all four serotypes at the same time, the vaccine may avoid the problems associated with ADE after a dengue virus infection. In the Philippines, 800,000 youngsters received the vaccination. After coming into contact with the dengue virus in the community, fourteen vaccinated youngsters perished. The children’s antibody responses were not capable of neutralizing the natural virus circulating in the population, according to the theory. As a result, the vaccination was only advised for children over the age of 9 who had already been exposed to the virus.
ADE and Coronavirus
Amongst RNA viruses, SARS-CoV-2 coronavirus, is responsible for the current Covid-19 epidemic. Following SARS in 2002-2003 and MERS in 2012, Covid-19 is the third major coronavirus-induced pandemic in the last 20 years.
The pandemic’s challenges have necessitated speedy vaccine research, so it’s critical to understand why it takes so long to produce an effective vaccine. One of the difficulties with coronaviruses is that they have a high degree of similarity, which increases the risk of cross-reaction between antibodies generated in the body, leading to ADE.
ADE has been known to stymie vaccine research for SARS, and it is likely to be an issue for Covid-19 as well. Researchers are working hard to create a safe and effective vaccine that can precisely destroy the SARS-CoV-2 viruses without cross-reacting with other comparable viruses, using lessons learned from related coronaviruses and technological breakthroughs. The creation of such vaccinations would greatly aid in the containment of the epidemic.
Conclusion
ADE of infection has become a major problem for disease control by immunization for several viruses. As a result, many methods to the production of vaccinations with minimal or no risk of ADE have been taken. It is critical to identify viral epitopes linked to ADE or neutralization for this aim. Furthermore, a thorough knowledge of the cellular processes that occur following viral entrance by ADE has become critical for the development of effective interventions. The processes of ADE, on the other hand, are still a mystery.
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References:
- Kulkarni, R. (2020). Antibody-dependent enhancement of viral infections. In Dynamics of Immune Activation in Viral Diseases (pp. 9-41). Springer, Singapore. . https://doi.org/10.1007/978-981-15-1045-8_2
- Balsitis, S. J., Williams, K. L., Lachica, R., Flores, D., Kyle, J. L., Mehlhop, E., Johnson, S., Diamond, M. S., Beatty, P. R., & Harris, E. (2010). Lethal antibody enhancement of dengue disease in mice is prevented by Fc modification. PLoS pathogens, 6(2), e1000790. https://doi.org/10.1371/journal.ppat.1000790
- Lee, W., Wheatley, A., Kent, S., &DeKosky, B. (2020). Antibody-dependent enhancement and SARS-CoV-2 vaccines and therapies. Nature Microbiology, 5(10), 1185-1191. https://doi.org/10.1038/s41564-020-00789-5
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