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While we are often reassured that most viral illnesses are `self-limiting' diseases, which will resolve over time, we continue to see evidence that some viral infections can produce significant long-term sequelae, including neurogenerative diseases.In the decade following the 1918 H1N1 pandemic - which killed tens of millions of people - the world experienced another type of epidemic; an explosion in cases of Encephalitis Lethargica, and Parkinson's disease, affecting millions (see The Lancet: COVID-19: Can We Learn From Encephalitis Lethargica?).
Its legacy was depicted in the 1990 fictionalized movie Awakenings, which was based on Oliver Sacks' 1973 memoir. In it, he described patients who had been comatose for 40 years who were treated with L-DOPA in the 1960s, and briefly recovered, only to slip back into a catatonic state.
While a direct link to the 1918 pandemic has never been established, similar outbreaks have been reported throughout history, including febris comatosa which sparked a severe epidemic in London between 1673 and 1675, and in the wake of the 1889–1890 influenza pandemic, a severe wave of somnolent illnesses (nicknamed the "Nona") appeared in Italy.
Very early in the 2020 COVID pandemic we began to see concerns raised over potential long-term neurological damage due to the SARS-CoV-2 virus (see J. Neurology: COVID-19 As A Potential Risk Factor For Chronic Neurological Disorders), and 5 years later we continue to see evidence of substantial sequelae.
In early 2023, in Neuron: Virus Exposure and Neurodegenerative Disease Risk Across National Biobanks, we looked at a large study, published in Cell Neuron, which found a statistical linkage between viral illnesses and developing neurodegenerative diseases later in life.
Viral encephalitis has been closely associated with the later development of neurodegenerative diseases and persistent viral infections of the CNS can result in severe and debilitating symptoms. Further, persistent infections may result in the development of autoreactive lymphocytes and autoimmune mediated tissue damage. Diagnosis of persistent viral infections of the CNS remains challenging and treatment options are limited.
The development of additional testing modalities as well as novel antiviral agents and vaccines against these persistent infections remains a crucial research goal.
- Researchers found associations between certain viral illnesses and the risk of Alzheimer’s and other neurodegenerative diseases.
- The results suggest that some neurodegenerative disease might be avoided by preventing infection with influenza and other viruses.
In a breakthrough a dozen years ago, human neural organoids (aka hNOs) were first created from lab-grown stem cells, which can simulate the architecture and functionality of the human brain (cite).
This made it possible to monitor, in real time, the pathogenic impact of viral infections on `living' brain tissue (see here, here, here, and here). While not a perfect analog for the human brain, these lab grown organoids provide a useful in vitro model for studying brain development and neurological disorders.
All of which brings us to a new study, published over the weekend in Nature Comms, which - using hNOs - describes how the Monkeypox virus can spread within these human neural organoids, and lead to neuronal death.
While considered a relatively mild `self-limiting' disease, Mpox clade IIb infections have been linked to more serious illness (see Neurological manifestations of an emerging zoonosis-Human monkeypox virus: A systematic review by Sajjad Ahmed Khan, Surya Bahadur Parajuli, Vivek K Rauniyar )
Monkeypox virus spreads from cell-to-cell and leads to neuronal death in human neural organoids
Isabel Schultz-Pernice, Amal Fahmi, Francisco Brito, Matthias Liniger, Yen-Chi Chiu, Teodora David, Blandina I. Oliveira Esteves, Antoinette Golomingi, Beatrice Zumkehr, Markus Gerber, Damian Jandrasits, Roland Züst, Selina Steiner, Carlos Wotzkow, Fabian Blank, Olivier B. Engler, Artur Summerfield, Nicolas Ruggli, David Baud & Marco P. Alves
Nature Communications volume 16, Article number: 5376 (2025) Cite this article
Abstract
In 2022-23, the world witnessed the largest recorded outbreak of monkeypox virus (MPXV). Neurological manifestations were reported alongside the detection of MPXV DNA and MPXV-specific antibodies in the cerebrospinal fluid of patients.Here, we analyze the susceptibility of neural tissue to MPXV using human neural organoids (hNOs) exposed to a clade IIb isolate. We report susceptibility of several cell types to the virus, including neural progenitor cells and neurons. The virus efficiently replicates in hNOs, as indicated by the exponential increase of infectious viral titers and establishment of viral factories.Our findings reveal focal enrichment of viral antigen alongside accumulation of cell-associated infectious virus, suggesting viral cell-to-cell spread. Using an mNeonGreen-expressing recombinant MPXV, we confirm cell-associated virus transmission. We furthermore show the formation of beads in infected neurites, a phenomenon associated with neurodegenerative disorders. Bead appearance precedes neurite-initiated cell death, as confirmed through live-cell imaging.Accordingly, hNO-transcriptome analysis reveals alterations in cellular homeostasis and upregulation of neurodegeneration-associated transcripts, despite scarcity of inflammatory and antiviral responses. Notably, tecovirimat treatment of MPXV-infected hNOs significantly reduces infectious virus loads.Our findings suggest that viral disruption of neuritic transport drives neuronal degeneration, potentially contributing to MPXV neuropathology and revealing targets for therapeutic intervention.
(SNIP)
Taken together, we show that human neural tissue, modeled in a complex 3D environment, is susceptible to infection with a contemporary clade IIb MPXV isolate. We show that viral replication factories are successfully established, resulting in a productive replication of MPXV within organoid cells. Furthermore, we find that viral antigen localizes not only to cell somata, but also to filaments of variable nature.
We propose that MPXV preferentially spreads from cell-to-cell, exploiting not only previously described mechanisms but also through neuritic transport, as demonstrated through live-cell imaging visualization of virus propagation dynamics. We furthermore report neuritic bead formation in virus-harboring axons and dendrites, previously documented to represent sites of virus egress and cell-to-cell transmission, as well as signs of neuronal injury.
Notably, bead formation precedes virus-induced neuronal death, which is initiated through neurite degeneration. The transcriptional landscape of MPXV-infected neural cultures suggests repurposing of tissue to favor viral propagation, characterized by disrupted cell homeostasis, limited antiviral and inflammatory responses, and upregulation of transcripts associated with neurodegenerative processes and synaptic reorganization.
Notably, tecovirimat treatment effectively limits viral spread but does not rescue the deleterious effects of neuron-to-neuron MPXV dissemination. Our findings identify a novel mechanism of MPXV spread in human neural tissue, shed light on potential factors contributing to mpox-encephalitis neuropathology, and provide a foundation for further exploration of orthopoxvirus neurobiology.(Continue . . . )
This press release from the University of Bern.
Can the monkeypox virus infect the human brain?
A new study led by researchers from the Institute of Virology and Immunology (IVI) and the University of Bern in collaboration with the Lausanne University Hospital and the Spiez Federal Laboratory shows that the monkeypox virus can spread efficiently in brain organoids, causing neuronal cell death. The study provides important insights into a previously unexplored aspect of MPXV infections.
(SNIP)
A team of researchers from the Institute of Virology and Immunology (IVI) and the University of Bern, in collaboration with the Lausanne University Hospital and the Spiez Federal Laboratory, has demonstrated for the first time that the MPXV can efficiently spread from cell to cell in brain organoids, leading to neuronal cell death. The study, supported by the Multidisciplinary Center of Infectious Diseases (MCID) at the University of Bern, was recently published in the journal Nature Communications.
One of the reasons why I get the flu shot every year, have stayed current with COVID shots - and still wear a mask in crowded indoor places - is that each year the evidence linking repeated viral infections to neurodegenerative diseases grows stronger.
While I can't do anything about my age, genetics, or past viral exposures, these proactive measures may help protect me going forward.
At least, that's the hope.
