The Ebola virus can lead to recurrent infections even after treatment

The big idea

The Ebola virus can hide in the brains of monkeys that have recovered after medical treatment without causing symptoms and lead to recurrent infections, according to a study by a team I led that was published in the journal Science Translational Medicine.

Ebola is one of the deadliest infectious disease threats known to humankind, with an average fatality rate of about 50%. Ebola is known for its high level of viral persistence, meaning the virus remains lurking in the body even after a patient has recovered. But where this hiding place remains largely unknown.

In 2021, there were three Ebola outbreaks in Africa, all linked to previously infected survivors. Ebola also reemerged in Guinea that same year, linked to a survivor of the 2013-2016 Ebola outbreak.

We wanted to better understand where the Ebola virus “hides” in the body of survivors and what triggers recurrent infections. So we examined 36 rhesus monkeys that had been treated for Ebola with monoclonal antibody therapy, a type of treatment that helps the immune system mount an attack against an infection. These monkeys were deemed fully recovered with no symptoms of infection or detectable virus in their blood.

When we looked more closely at the tissues of different organs under a microscope, however, we found that about 20% of recovered monkeys still had visible Ebola virus located exclusively in the ventricular system of the brain. This brain region produces, circulates, and stores cerebrospinal fluid, which protects, supplies nutrients to, and removes waste products from the brain.

Importantly, despite being asymptomatic at the start of our study, two of the monkeys we observed developed Ebola symptoms before dying at 30 and 39 days after their initial infection, respectively. Our findings suggest that the Ebola virus can hide dormant in the brains of survivors even after treatment, and the virus can reactivate and cause fatal infections later on.

Why it matters

Treatment with monoclonal antibodies is the current standard of care for Ebola. But recurrent infections can occur even after apparently successful treatment, and patients can inadvertently transmit the virus and cause new outbreaks.

Our study underscores the importance of careful long-term medical follow-up of successfully treated Ebola survivors to counter the individual and public health cost of recurrent disease. This follow-up, however, will need to be conducted in a way that does not further stigmatize survivors of the disease.

What still isn’t known

We still don’t know why the Ebola virus persists in the brain and causes recurrent infections. It is also unclear whether this persistence might be related to monoclonal antibody treatments, and whether other types of therapies, such as antivirals, might produce a different effect. Researchers are still looking into what triggers relapses and whether there might be other parts of the body that may act as reservoirs.

What’s next

Our work highlights the need to deeply investigate why the Ebola virus persists in the brain. Because the brain is less accessible to monoclonal antibodies, treatments combining both monoclonal antibodies and antiviral drugs may help prevent and clear persistent Ebola infection and related diseases in the brain. Analyzing viral persistence at the molecular level may provide more insight.

Kevin Zeng, Principal Investigator of Infectious Diseases, U.S. Army Medical Research Institute of Infectious Diseases

This article is republished from The Conversation under a Creative Commons license. Read the original article.

Abstract
Effective therapeutics have been developed against acute Ebola virus disease (EVD) in both humans and experimentally infected nonhuman primates. However, the risk of viral persistence and associated disease recrudescence in survivors receiving these therapeutics remains unclear. In contrast to rhesus macaques that survived Ebola virus (EBOV) exposure in the absence of treatment, we discovered that EBOV, despite being cleared from all other organs, persisted in the brain ventricular system of rhesus macaque survivors that had received monoclonal antibody (mAb) treatment. In mAb-treated macaque survivors, EBOV persisted in macrophages infiltrating the brain ventricular system, including the choroid plexuses. This macrophage infiltration was accompanied by severe tissue damage, including ventriculitis, choroid plexitis, and meningoencephalitis. Specifically, choroid plexus endothelium-derived EBOV infection led to viral persistence in the macaque brain ventricular system. This resulted in apoptosis of ependymal cells, which constitute the blood–cerebrospinal fluid barrier of the choroid plexuses. Fatal brain-confined recrudescence of EBOV infection manifested as severe inflammation, local pathology, and widespread infection of the ventricular system and adjacent neuropil in some of the mAb-treated macaque survivors. This study highlights organ-specific EBOV persistence and fatal recrudescent disease in rhesus macaque survivors after therapeutic treatment and has implications for the long-term follow-up of human survivors of EVD.