Ebola virus can hide away in the brain

Ebola virus (EBOV) causes one of the deadliest infectious diseases known to humankind. Worryingly, recent outbreaks in Africa have been linked to the recurrence of persistent infection (recrudescence) in patients who had already survived previous infection.

According to groundbreaking new research, EBOV can persist in certain areas of the brain, which is an immune-privileged organ. Until now, the exact “hiding place” of the persistent virus in the body, as well as the underlying pathology of the recurring disease, was unknown.

Published in Science Translational Medicine, the study found that even after treatment with monoclonal antibodies (mAbs), EBOV can remain latent in the ventricular system – fluid filled spaces of the brain – and re-emerge to cause fatal disease in rhesus macaques.

“Ours is the first study to reveal the hiding place of brain Ebola virus persistence and the pathology causing subsequent fatal recrudescent Ebola virus–related disease in the nonhuman primate model,” says senior author Dr Xiankun (Kevin) Zeng, of the US Army Medical Research Institute of Infectious Diseases (USAMRIID).

Dr Jun Liu of USAMRIID, co-first author, adds that “the persistent Ebola virus may reactivate and cause disease relapse in survivors, potentially causing a new outbreak.”

Recurring infection has been previously reported in human survivors of the disease – a British nurse experienced relapse in the brain and suffered from meningoencephalitis nine months after recovering from severe Ebola virus disease, while the 2021 EBOV outbreak in Guinea re-emerged from a persistently infected survivor of the previous major outbreak, at least five years prior.

“We found that about 20% of monkeys that survived lethal Ebola virus exposure after treatment with monoclonal antibody therapeutics still had persistent Ebola virus infection – specifically in the brain ventricular system, in which cerebrospinal fluid is produced, circulated and contained – even when Ebola virus was cleared from all other organs,” says Zeng.

In particular, two monkeys that initially recovered after treatment with mAbs subsequently died with severe inflammation and massive EBOV infection in the brain ventricular system.

Ebola virus stain. Credit dr. Xiankun kevin zeng usamriid 850
Ebola virus (brown) relapses in the brain ventricular system and adjacent neuropil in a rhesus monkey that survived Ebola virus exposure after treatment with monoclonal antibodies (cell nuclei counterstained in blue). Credit: Dr. Xiankun (Kevin) Zeng, USAMRIID.

The researchers had previously shown that the virus can hide and persist in other specific regions of immune-privileged organs (such as the vitreous chamber of the eyes and the seminiferous tubules of the testes), despite being cleared from all other organs.

Global research efforts have led to regulatory approval for two vaccines to protect against infection, and two mAbs – Inmazeb and Ebanga – were approved for treatment in adults and children by the US Food and Drug Administration in late 2020.

These therapeutics are now part of the standard of care for EBOV-infected patients, though this new research highlights the need to check back in with survivors to prevent deadly infection recurrence.

“Fortunately, with these approved vaccines and monoclonal antibody therapeutics, we are in a much better position to contain outbreaks,” says Zeng. “However, our study reinforces the need for long-term follow-up of Ebola virus disease survivors – even including survivors treated by therapeutic antibodies – in order to prevent recrudescence.

“This will serve to reduce the risk of disease re-emergence, while also helping to prevent further stigmatisation of patients.”

The 2013–16 Ebola outbreak in West Africa was the subject of the film Think like a scientist: natural selection in an outbreak, which was featured in the 2017 SCINEMA International Science Film Festival. In it computational geneticist Dr Pardis Sabeti and disease ecologist Dr Lina Moses bring us to the front line of the epidemic and explain the science behind how this event became the largest Ebola outbreak in history.

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