Ebola virus continues active replication in brain tissue models

Three-dimensional cerebral organoids suggest that Ebola virus can establish long-term infection in the human brain.

The Ebola virus causes Ebola virus disease, which is a severe and often fatal infection. Previous research has shown that Ebola virus can persist in certain tissues after recovery, sometimes for months or years, although the mechanisms underlying this persistence have remained unclear. Researchers from the Icahn School of Medicine at Mount Sinai in New York and the Bernhard Nocht Institute for Tropical Medicine (BNITM) in Hamburg, Germany, used cerebral organoid models to investigate how Ebola virus and related filoviruses may persist in central nervous system tissues.

'These cerebral organoids enable us to investigate in detail the mechanisms that Ebola virus and other filoviruses use to persist in the human central nervous system,' said Dr Lina Widerspick, first author of the study published in Nature Microbiology and former researcher at the BNITM. '…we can gain insights that help us improve our understanding of the long-term effects of persistence like the severe and sometimes fatal inflammation seen in Ebola virus disease survivors with meningoencephalitis.'

The study found that the Ebola virus could establish a long-term infection in the cerebral organoid model, where it continued to replicate and spread between cells for more than 120 days after infection. The findings suggest that the virus may persist in central nervous system tissue through a state of 'productive persistence', in which it continues to replicate at low levels rather than remaining dormant.

In the organoid model, Ebola virus infected neurons, astrocytes and microglia, a type of specialised immune cell found in the brain. Researchers also observed evidence of ongoing viral replication and the production of defective viral genomes: shortened viral genome segments that have previously been linked to persistent infections.

Although infected organoids produced elevated levels of pro-inflammatory cytokines associated with the innate immune response, the virus was not fully cleared and signs of local inflammation persisted.

'This observation is consistent with the fact that some Ebola virus disease survivors develop inflammation of the eye, meninges or brain months after infection with Ebola virus,' said Professor César Muñoz-Fontela, research group leader at the BNITM and co-last author of the study.

Researchers also identified viral genetic mutations that accumulated over time within infected organoids. The authors suggest that these genetic changes, together with defective viral genomes, may contribute to long-term viral persistence, although their precise role remains unclear. Some of the mutations identified have not previously been reported in Ebola virus disease survivors and require further investigation.

'Our work in human cerebral organoids highlights the potential of this model system to investigate persistent infections in immune-privileged tissues,' said Professor Gustavo Palacios from the Icahn School of Medicine, a co-author of the study. 'Further studies are now important to investigate the long-term interactions between virus and host, …and to deepen our understanding of filoviral persistence mechanisms.'