COVID-19: Bats and Interferon

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Why Bats Make Such Good Viral Hosts

Photo by Peter Neumann on Unsplash

Bats carry and transmit some of the world’s deadliest zoonotic viruses: Ebola, Marburg, Nipah, and the pathogen behind severe acute respiratory syndrome, SARS coronavirus, to name a few. What has puzzled researchers for a long time is why bats don’t appear to get sick from their unusually high microbial loads. The question has been nagging Peng Zhou, a virologist at China’s Wuhan Institute of Virology, for more than a decade, ever since he took part in a survey of bat populations in southern China. Zhou and his colleagues were looking for the strain of the SARS coronavirus responsible for the 2003 outbreak that sickened more than 8,000 people worldwide and killed nearly 800. “We started to think, why bats?” he says.

Other researchers have suggested that bats’ super-tolerance might have something to do with their ability to generate large repertoires of naïve antibodies, or that flight ramps up the animals’ body temperatures to a fever-like state that helps fight off infections. But in 2013, Zhou and his colleagues stumbled across another clue during a comparative genomics study of two distantly related bat species. The genes that showed some of the strongest evidence of positive selection, the team found, appeared to be related to DNA damage and innate immunity . “We thought we needed to go further and work on the molecular mechanics,” says Zhengli Shi, Zhou’s colleague at the Wuhan Institute and a coauthor on the study.

The team decided to focus on a protein known to lie at the center of several molecular pathways involved in the vertebrate innate immune response. STING, or STimulator of INterferon Genes, detects pieces of DNA where they shouldn’t be: in the cellular cytoplasm. This free DNA can occur through infection by DNA viruses, and potentially also RNA viruses. Once activated, STING triggers rapid production of signaling proteins called interferons that help launch an immune response against infection.

Sequencing of the gene encoding STING in a handful of mammal species revealed a striking abnormality in the bat version: a mutation — responsible for a single replacement of a serine residue with another amino acid at an important phosphorylation site in the STING protein — was universal across 30 bat species. By contrast, the serine was retained in 10 other vertebrate species, including zebra-fish, chickens, and nonflying mammals such as the house mouse and cow.

n a series of subsequent in vitro experiments, the researchers found that bat STING — isolated from the Chinese rufous horseshoe bat, Rhinolophus sinicus — produced a significantly milder interferon response compared to its mouse counterpart when treated with a known activator molecule in vitro. The team could encourage the production of higher levels of interferons if they corrected the mutation to restore the serine residue. Conversely, they observed a decrease in interferon production by human STING after they pulled the serine out .

The findings suggest that this mutation dampens bats’ interferon-activating pathway just enough to stop the animals’ immune systems from going into overdrive. Many viruses are so deadly to humans and other animals because they trigger an uncontrollable storm of interferons and other inflammation-inducing molecules, overwhelming the immune system, Zhou explains. But, by virtue of this mutation, bats can avoid such chaos, and instead can tolerate the same viruses. “That has a very significant meaning for bats,” he says.

Despite STING’s role in viral responses, Zhou believes that the mutation may be conserved in bats for a different reason, one related to another aspect of bats’ livelihood. Fragments of the bats’ own DNA can also be released into their cells’ cytoplasm as a byproduct of the strenuous effort bats make during flight, Zhou says. This has led him to the hypothesis that the mutation originally provided an evolutionary advantage to bats by preventing their immune systems from boiling over every time the animals fly.

Interferons as a Potential Treatment

Interferons are a family of naturally-occurring proteins that are made and secreted by cells of the immune system (for example, white blood cells, natural killer cells, fibroblasts, and epithelial cells). Three classes of interferons have been identified:

  1. alpha,
  2. beta, and
  3. gamma.

Each class has many effects, though their effects overlap. Commercially available interferons are human interferons manufactured using recombinant DNA technology. The mechanism of action of interferon is complex and is not well understood. Interferons modulate the response of the immune system to viruses, bacteria, cancer, and other foreign substances that invade the body. Interferons do not directly kill viral or cancerous cells; they boost the immune system response and reduce the growth of cancer cells by regulating the action of several genes that control the secretion of numerous cellular proteins that affect growth.

Interferon beta-1a, currently in use to treat multiple sclerosis, and interferon alfa-2b are both under investigation as potential treatments for people with COVID-19 coronavirus disease, the deadly respiratory pandemic caused by the SARS-nCoV-2 virus.

  • Essentially, when confronted with a virus, each cell shoots an emergency flare of interferon to tell the immune system to marshall its defenses.
  • Interferon Beta 1a, specifically, activates macrophages that engulf antigens and natural killer cells (NK cells), a type of immune T-Cell.
  • Those cells are integral in the innate immune system.
  • The theory is, interferon may be able to make the immune system stronger by turning on dormant parts and directing them toward the defense against SARS-nCoV-2’s assault.

The problem is, when interferons ramp up the immune system, COVID-19’s flu-like symptoms are likely to become worse before they get better; interferon naturally occurring in the body is responsible for all flu-like symptoms to begin with, whether you have the coronavirus or a common cold.

So, if someone is already on a ventilator and symptoms are about to overwhelm them, giving them an interferon-based medicine could be catastrophic. This is why interferon therapies for viral infections are typically a last resort — the potential for dire side effects.

Studies around the world, including a huge WHO study, are looking at different interferons to treat COVID-19 coronavirus, but no existing COVID-19 drug trials in the U.S. included interferons as of April 7, 2020.

It is possible there is a hesitance to use interferon in America because it was used in the late 1990s and early 2000s to treat Hepatitis C, and its side effects caused a lot of injury to U.S. patients.

Clinicians were lucky if they saw a 30% cure rate treating Hep C with interferon, but the side effects were severe, including:

  • Drop in white blood cell levels,
  • liver problems, and
  • psychiatric issues.

People would become suicidal, fall into deep depressions.

Conclusion

Clearly , eating bats should be avoided as much as possible to avoid such pandemics in future. As the world is slowly recovering from these hard times, Many countries have already claimed for the Vaccine.

Interferons can be primary human immune cell booster and can actually be very helpful in regulating host antiviral activities.