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The Extracellular Letter to COVID-19

The Extracellular Letter to COVID-19

Tiny, spherical pods float from one cell to another through the crowded space of other cells and fluids such as blood and mucus. These package-like pods are unassuming. They slip past other cells and complex tissues, intent on delivering their contents to the intended recipient.

After pinching off from the cell, these packets carry specific content from the cells they came from, much like a letter in the mail.

These postal pockets that are ferried between cells are known by scientists as extracellular vesicles. Since they carry contents from within a cell, scientists believe these packets can provide clues about pathogens or diseases that may be harboring within cells.

For decades, this valuable insight has led researchers to explore the possibilities extracellular vesicles might hold for disease diagnosis, monitoring and even treatment.

Amid the current pandemic, some scientists are exploring how extracellular vesicles could be used to detect, treat or monitor the virus known as SARS-CoV-2 and its ensuing respiratory illness, COVID-19. Johns Hopkins Medicine researcher Kenneth Witwer, Ph.D., has studied extracellular vesicles for much of his career and is the executive chair of science and meetings for the International Society for Extracellular Vesicles.

Witwer suggests that extracellular vesicles may be able to help researchers studying COVID-19 in three ways.

Building a Better Vaccine

Fundamentally, vaccines are small samples of pathogens, nasty microscopic structures that have unique molecules on their surface to identify their foreign origins. An inactivated or weakened version of these pathogens is injected into the body so that our immune system can become familiar with them. After vaccination, if the pathogen does attack, the body is prepared to fight it. Extracellular vesicles have been used for vaccine development for many decades.

In the 1980s, scientists in Cuba developed the first extracellular vesicle vaccines from bacteria. When introduced to an animal host, bacteria-based vesicles cannot replicate and therefore can’t infect the animal, but because they carry with them part of the surface of the bacteria, they still elicit an immune response.

According to Witwer, bacterial vesicles are particularly advantageous to vaccine development because they create a stronger immune response than many other pathogens. “When you make a vaccine you want to make sure the immune system is really going to respond to it,” explains Witwer. “Bacterial vesicles sort of act as their own adjuvants,” the chemical substance mixed into vaccines to trigger a stronger immune response when the pathogen simply isn’t strong enough, making them a viable candidate for a potential COVID-19 vaccine.

Between bacteria-based vesicles and extracellular vesicles derived from mammalian cells, scientists have many options when engineering vaccines, says Witwer. “We can put things on the surface of vesicles that will adjust the effects of the vaccine, or we can target vesicles to specific cells. We can even add factors that help the extracellular vesicle avoid being cleared too quickly from the body.” Extracellular vesicles are a promising platform for vaccines, including a COVID-19 vaccine, because of their easy manipulation, “plug-and-play” capabilities.

Repairing Tissues and Avoiding an Auto-immune Response

Among the most primitive cells in the body that can become several types of cells, such as muscle or skin cells, are mesenchymal stem cells. These cells have special properties that allow them to renew themselves and dampen an immune response in certain instances.

Extracellular vesicles that bud from mesenchymal stem cells may be able to repair the lung damage associated with COVID-19 and prevent a potentially fatal autoimmune response that clinicians have observed among people hospitalized for COVID-19.

Mesenchymal stem cell extracellular vesicle–based therapies are already being tested in COVID-19 patients. One such study in Wuhan, China, where the first cases were reported, is set to conclude in May 2020. Witwer, who serves as an associate editor of the Journal of Extracellular Vesicles, warns, however, that historically, some mesenchymal stem cell extracellular vesicle–based therapies have gone underregulated, leading to unsafe practices.

According to Witwer, “there have been problems in the mesenchymal stem cell extracellular vesicle field where companies decide to use these therapies without proper regulatory oversight.” Witwer explains, “extracellular vesicles are not exempt from oversight, and the FDA has already begun to intervene on such studies.”

Prognosis and Monitoring

A small bit of body fluid, such as mucus in the lungs, is bound to contain extracellular vesicles. When examining genetic material called RNA, a close cousin of DNA, from extracellular vesicles collected from the lungs, researchers can use the information as a readout on the health of the lungs. RNA has the potential to reveal whether the immune system is effectively responding in the body and potentially if the patient has experienced a second COVID-19 infection.

“A little RNA goes a long way,” says Witwer. Scientists can take scant amounts of RNA and magnify it, in a process called amplification, to examine thousands of genes.

“Some might ask why focus on RNA within extracellular vesicles when you can get RNA directly from mucus or blood,” says Witwer. “RNA can be collected from several different types of carriers, but only extracellular vesicles give clinicians the edge of knowing what tissue the RNA came from.”

In COVID-19, these implications go beyond disease monitoring in individuals. COVID-19 reinfection rates across populations can inform broader public health decisions.
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