Ebola Virus Hides in the Central Nervous System, According to New Research Led by Microbiologists at the Icahn School of Medicine at Mount Sinai
International team uses cerebral organoids to better understand virus biology
Following infection, Ebola virus can survive unnoticed in the human body for months or even years, hiding in areas with little immune surveillance like the central nervous system. In doing so, it poses the danger of triggering an Ebola virus disease relapse or even a new outbreak.
Using a cerebral organoid model, researchers from the Icahn School of Medicine at Mount Sinai and the Bernhard Nocht Institute for Tropical Medicine (BNITM), together with other collaborators, gained valuable insights into the mechanisms of Ebola virus persistence. The findings were recently published in Nature Microbiology.
Ebola virus is a filovirus that causes Ebola virus disease, a severe and often fatal infection. Even if those affected survive the acute phase of the disease, the virus can remain in the body. Infectious Ebola virus has been detected in semen for months or even a year after infection. The virus can also persist in other immune-privileged organs such as the central nervous system, particularly the brain. Immune-privileged means that the immune system reacts in a weakened and controlled manner in these areas in order to protect sensitive tissue. As a result, it cannot always eliminate the virus completely. This persistent viral presence increases the risk of later inflammatory disease and relapses in individual patients and, albeit rarely, of retransmission to others.
Cerebral organoids suitable for investigating Ebola persistence
Little is known about the mechanisms that allow Ebola virus to survive long-term in its host. Does it persist in tissues or in individual cells? Does it produce new infectious particles? Does it alter its genome to evade detection by our immune system? Because research on the human central nervous system is highly complicated, suitable model systems are required in order to answer these scientific inquiries. To that end, the research team successfully used an established cerebral organoid model to perform long-term infection studies. To make these organoids, they stimulated human induced pluripotent stem cells in a way that allowed them to develop into spherical brain-like structures consisting of various types of cells of the central nervous system.
“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. Through experiments in this model system, 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,” explains Lina Widerspick, PhD, first author of the publication and former researcher at the BNITM. She carried out part of the experiments during a research visit to the Integrated Research Facility-Frederick of the National Institutes of Health in the United States. She is now based at the Bundeswehr Institute of Microbiology in Munich, Germany.
Moreover, organoids give the unique opportunity to study this phenomenon in a human background rather than an animal model. This may help in reassessing and optimizing treatments such as antivirals, and further opens avenues to reduce the use of animal models in infectious disease research.
Ebola virus can survive long-term in cerebral organoids
The researchers showed that Ebola virus and other filoviruses, such as Sudan, Reston, and Marburg virus, can replicate in cerebral organoids for up to 120 days. They also found that Ebola virus infected various cell types in the cerebral organoids—neurons as well as astrocytes. Microglia, the brain’s immune cells, were also attracted to the site and infected by the virus. Ebola virus was able to spread in the cerebral organoids in two ways: directly from an infected cell to a neighboring cell and by budding from the host cell, which is the classical way the virus spreads. Thus, this represents a “productive persistence,” meaning that Ebola virus is not present in an inactive state within cells, but remains infectious.
The cerebral organoids produced pro-inflammatory cytokines, but the immune response was unable to successfully eliminate the virus during the persistent infection. “We observed elevated immune and inflammatory responses in the late stages of cerebral organoid culture. We therefore conclude that a persistent Ebola virus infection in immune-privileged tissues can lead to local inflammation. 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,” says César Muñoz-Fontela, PhD, head of the Virus Immunology research group at BNITM and co-last author of the study.
How Ebola adapts to survive
Defective viral genomes are considered a well-known mechanism used by many viruses to suppress their replication. This enables the viruses to survive in the body in an attenuated but long-lasting form. It is also known that the Ebola virus genomes mutate when they replicate for a long time, since their genetic machinery cannot proofread the genomes as human machinery would do. The research team has now identified defective viral genomes and particles, and mutations in the Ebola virus genomes in late-stage persistently infected cerebral organoids.
“Many of these mutations had been proposed to reduce or prevent viral replication in naturally occurring infections. Because Ebola virus behaves similarly in this model system to how it does in human infections, this underscores the suitability of our cerebral organoids for investigating filovirus persistence,” explains Gustavo Palacios, PhD, Professor of Microbiology at the Icahn School of Medicine, co-last author of the publication, and an expert on Ebola virus genomics. The researchers also identified mutations that have not been described in Ebola virus disease survivors. Further investigations are now needed to determine whether these mutations are causally linked to filovirus persistence.
“Our work in human cerebral organoids highlights the potential of this model system to investigate persistent infections in immune-privileged tissues,” said Dr. Palacios. “Further studies are now important to investigate the long-term interactions between virus and host, expanding our studies towards less-studied filoviruses like Reston, Taï Forest, Bombali, and Bundibugyo virus, and to deepen our understanding of filoviral persistence mechanisms.”
About the Icahn School of Medicine at Mount Sinai
The Icahn School of Medicine at Mount Sinai is internationally renowned for its outstanding research, educational, and clinical care programs. It is the sole academic partner for the seven member hospitals* of the Mount Sinai Health System, one of the largest academic health systems in the United States, providing care to New York City’s large and diverse patient population.
The Icahn School of Medicine at Mount Sinai offers highly competitive MD, PhD, MD-PhD, and master’s degree programs, with enrollment of more than 1,200 students. It has the largest graduate medical education program in the country, with more than 2,700 clinical residents and fellows training throughout the Health System. The Graduate School of Biomedical Sciences offers 12 degree-granting programs, conducts innovative basic and translational research, and trains more than 470 postdoctoral research fellows.
Ranked 11th nationwide in National Institutes of Health (NIH) funding, the Icahn School of Medicine at Mount Sinai is among the 90th percentile of U.S. private medical schools in Sponsored Programs Direct Expenditures per Principal Investigator, according to the Association of American Medical Colleges. More than 6,900 scientists, educators, and clinicians work within and across dozens of academic departments and multidisciplinary institutes with an emphasis on translational research and therapeutics. Through Mount Sinai Innovation Partners (MSIP), the Health System facilitates the real-world application and commercialization of medical breakthroughs made at Mount Sinai.
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