Ebola resurfaced: some viruses are never really gone

Seven years after the last Ebola epidemic in Guinea, the virus has once again raised its ugly head, with 23 cases and 12 deaths in a new outbreak. They were caused not by a spillover of the virus from animals to humans, but by latent Ebola hiding inside surviving patients.

What is Ebola?

Ebola virus disease (Zaire ebolavirus) is a rare but deadly virus that causes fever, diarrhea, and severe, uncontrollable bleeding as the blood loses its ability to clot.

The devastating disease kills up to 90% of the people it infects.

Ebola is a zoonotic virus, a common cause of epidemics. These viruses originate from animals – such as bats and chimpanzees – and are passed to humans when they come in close contact. The exact origin animal of Ebola is unknown.

From there, Ebola is transmitted between humans through contact with bodily fluid, such as blood and semen, either directly or indirectly on clothes, sheets and beds.

People remain infectious for as long as the blood contains the virus, but recovered men can continue to transmit it in semen for up to seven additional weeks.

There is currently no cure for Ebola, and the only two approved vaccines are in limited supply.

Latent Ebola resurgence in Guinea

In a recent study, published in Nature, researchers tracked the genetic lineage of a 2021 Ebola outbreak in Guinea, West Africa. They found that the outbreak was not the result of the disease jumping from animal to human, as normally happens, but originated from latent Ebola.

This ‘resurrected’ virus, transmitting from people who recovered from an Ebola outbreak five years ago, suggests that sometimes survivors still harbour the virus many years later.

“This is very surprising and very shocking,” César Muñoz-Fontela of the Bernhard Nocht Institute for Tropical Medicine in Germany told New Scientist. Muñoz-Fontela was in Guinea during the previous Ebola epidemic. “It’s like a relapse.”

Guinea had been Ebola-free since the end of the 2013–2016 outbreak in West Africa, in which 28,000 people were infected and 11,000 died.

The researchers compared the 2013–2016 viral strains to those in 14 individuals from the 2021 outbreak and found there were very few differences between the two.

This suggests it was caused by the same virus that was relatively inactive for five years and had a long period of latency where it didn’t replicate enough to accumulate new mutations.

The alternative option – where the virus independently jumped from animal to human again – doesn’t fit this data, because many more mutations would be expected in a new zoonotic strain.

What is virus latency?

Latency occurs when a virus, bacteria or fungus stops replicating and causing symptoms but remains dormant in the body.

Sometimes, a disease may infect somebody and not cause symptoms until many years later. Other times, a disease may manifest in one way early but have different symptoms later in life.

“Typically when we think of viruses that are latent, its about herpes virus,” says Sanjaya Senanayake, an infectious disease physician and a professor of medicine at the Australian National University.

This group includes genital herpes, cold sores, mono (kissing disease) and chicken pox.

“In that family of herpes viruses, there are eight viruses and they all are latent,” says Senanayake.

“Once you’ve been infected with them, they stick around in different parts of the body and they lie in wait. For a lot of people, they’ll never be heard from again.

“But the most common form of recurrence is when your chickenpox virus, varicella-zoster virus, sitting in the dorsal root ganglia cells in the spinal cord, suddenly has a resurgence.

“It comes back not as chickenpox, but as shingles.”

Why does latency occur?

The main reason virus latency may occur is to keep the virus, bacteria or fungus in the body. When a pathogen enters and is destroyed by the immune system, immunity often prevents that virus from getting a foot in the door again.

However, by hiding within the body, the pathogen has multiple chances of replicating and spreading at a later date. Here, the virus may remain dormant until the body is stressed and has a weaker immune system that the virus could bypass.

It is very hard to avoid the body’s defences, however, which may explain why so few viruses show latency.

How does Ebola evade the immune system?

Herpes virus is a variant made of DNA, which is a stable molecule that can survive for a long time. However, Ebola is a little different to herpes.

“Ebola is interesting because it’s an RNA virus, so you don’t classically expect latency with that,” says Senanayake.

Ordinarily, an RNA virus infects the body and hijacks cell machinery to replicate itself. As new virus builds up, symptoms occur, and the individual becomes infectious.

However, RNA viruses rely on the hijacked cells to replicate. They cannot survive for long, so if a virus stops replicating, the immune system will normally destroy it.

However, latent viruses avoid the immune system in a few ways.

The first involves a stabilised viral RNA that floats around inside the cell. The benefit of this is that the virus doesn’t need to get into the nucleus – which could trigger a whole army of defences – but also means it is susceptible to being digested by cellular enzymes.

The second method involves hiding in plain sight and integrating right into the DNA, where it can never truly be destroyed. However, for this to work, the virus needs to make it all the way into the most well-defended part of the cell – a feat for which HIV is well-known.

Beyond this, some viruses can also evade the immune system by hiding away in specific tissue that isn’t covered by the immune system.

“What we have found with Ebola is that the so-called immune privilege sites,” explains Senanayake.

“Even though it seems to be all-pervasive, there are certain areas that the immune system doesn’t go to, like the testicles, certain areas of the central nervous system, and the eyes.

“Those are areas where the virus could potentially lie later and come back.”

It was already known that latent Ebola could persist in patients – for one man, it persisted in semen for more than 500 days – but the length of this dormancy is unprecedented.

For this reason, few viruses are truly latent because they must possess the ability to cease all replication, hide from immune defences, and reactivate when triggered by an external activator such as stress.

In the case of this Ebola resurgence, further studies are needed to determine the mechanism that caused the virus to remain latent.

Virus latency is different to incubation period, where a person has the virus but hasn’t yet shown symptoms. In this case, the virus is still replicating, but hasn’t accumulated enough to cause symptoms.

The nature of latent the Ebola strain identified in Guinea

For true latency to be achieved, a virus must cease replication altogether.

However, the 2021 Ebola strains had some mutations that differed from the 2013–2016 strain. This means there was some replication during the five-year lull, but not enough to match a normal rate of evolution expected in a zoonotic virus.

Instead of going into complete hibernation, the strain may have instead replicated extremely slowly.

This could give it latency-like properties – it didn’t replicate enough to cause major symptoms and still had a later resurgence, but it didn’t become properly inactive.

However, the rate of evolution is generally relatively consistent and long-phase latency, preceded or followed by enough replication to accumulate a few mutations, may be a more accurate hypothesis, the authors explain in their paper.

Genetic data of previous outbreaks is scarce, however, making it difficult to confirm exactly what happened.

How is latent Ebola managed?

The resurgence of Ebola in 2021 highlights the need for long-term care for Ebola survivors.

“This has really turned our understanding of RNA viruses and latency on its head,” says Senanayake.

“It means we need a very low threshold for considering a diagnosis like Ebola in these cases. We can’t just say, ‘Oh look, there’s no active Ebola at the moment; this person had Ebola before so they are immune and it doesn’t make sense that they could transmit it to anyone.’”

This is especially necessary to consider if some people had previously caught Ebola but were asymptomatic until years later.

With this in mind, the authors of the study say that continued, portable genomic surveillance of survivors may help to catch cases before they become symptomatic and allow for early intervention – such as through use of anti-viral agents.

Local facilities also need to be built in countries that are at high risk of Ebola. This will ensure that virus tracking and vaccine supply are equitable.

Additionally, the researchers assert the need for social considerations of the survivors to ensure that they are safe within their community. In previous epidemics, some survivors were seen as heroes who had endured a great battle, but many were stigmatised as a source of danger and were blocked from housing and jobs.

“The other thing it is that it isn’t happening left right and centre,” says Senanayake.

“These are uncommon cases, but I think people like infectious diseases physicians, public health physicians and epidemiologists have to keep that in mind when these cases arrive, they don’t rise.”

Because of this, Ebola management must consider both the genetics and biology of Ebola as well as the health and social impacts of the disease.