SARS-CoV-2 infection and viral fusogens cause neuronal and glial fusion that compromises neuronal activity

Martínez-Mármol, Ramón; Giordano-Santini, Rosina; Kaulich, Eva; Cho, Ann-Na; Przybyla, Magdalena; Riyadh, M. Asrafuzzaman; Robinson, Emilija; Chew, Keng Yih; Amor, Rumelo; Meunier, Frédéric A.; Balistreri, Giuseppe; Short, Kirsty R.; Ke, Yazi D.; Ittner, Lars M.; Hilliard, Massimo A.

doi:10.1126/sciadv.adg2248

Cited by 31 publications

(25 citation statements)

References 80 publications

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“…3, Microglia), arguing that microglia are not a major target of infection. Occasional overlap (yellow) may be due to phagocytosis of debris from virus-infected cells may arise from the recently described fusion events (Martínez-Mármol et al, 2023). Despite being surrounded by infected neurons, most microglia retaining their ramified morphology, although some cells with bushy and amoeboid morphology were present (Fig.…”

Section: Resultsmentioning

confidence: 98%

Increased neurovirulence of omicron BA.5 and XBB variants over BA.1 in K18-hACE2 mice and human brain organoids

Stewart

Ellis

Yan

et al. 2022

Preprint

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A frequently repeated premise is that viruses evolve to become less pathogenic. This appears also to be true for SARS-CoV-2, although the increased level of immunity in human populations makes it difficult to distinguish between reduced intrinsic pathogenicity and increasing protective immunity. The reduced pathogenicity of the omicron BA.1 sub-lineage compared to earlier variants is well described and appears to be due to reduced utilization of TMPRRS2. That this reduced pathogenicity remains true for omicron BA.5 was recently reported. In sharp contrast, we show that a BA.5 isolate was significantly more pathogenic in K18-hACE2 mice than a BA.1 isolate, with BA.5 infection showing increased neurovirulence, encephalitis and mortality, similar to that seen for an original strain isolate. BA.5 also infected human cortical brain organoids to a greater extent than a BA.1 and original strain isolate. Neurons were the target of infection, with increasing evidence of neuron infection in COVID-19 patients. These results argue that while omicron virus may be associated with reduced respiratory symptoms, BA.5 shows increased neurovirulence compared to earlier omicron sub-variants.

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Section: Resultsmentioning

confidence: 98%

Increased neurovirulence of omicron BA.5 and XBB variants over BA.1 in K18-hACE2 mice and human brain organoids

Stewart

Ellis

Yan

et al. 2022

Preprint

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“…For COVID-19 research, several transgenic mice models engineered with human ACE2 (hACE2) simulate varying aspects of the disease, from lethal to non-lethal infections (Muñoz-Fontela et al, 2020). Those studies revealed the neural impact of the SARS-CoV-2 virus on both neurons and non-neuronal cells in the brain (e.g., (Song et al, 2021b; Fernández-Castañeda et al, 2022), including fusion of neurons and glial cells into syncytia with pathological function (Martínez-Mármol et al, 2023a). Furthermore, studies using non-human primates showed the neuroinvasive potential of SARS-CoV-2, and that neuronal damage is greater in older animals (Beckman et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, studies using non-human primates showed the neuroinvasive potential of SARS-CoV-2, and that neuronal damage is greater in older animals (Beckman et al, 2022). Additionally, brain organoids have provided invaluable insights into the neuroinvasive potential of the SARS-CoV-2, Zika, and Dengue virus (Abreu et al, 2018; Sutarjono, 2018; Pellegrini et al, 2020; Song et al, 2021a; Martínez-Mármol et al, 2023b).…”

Section: Discussionmentioning

confidence: 99%

“…For example, a recent study showed that SARS-CoV-2 infection can induce neurons and glia to fuse with neighbouring cells and create multinucleated syncytia, allowing for viral propagation from within one cell to the next (Martínez-Mármol et al, 2023a). That process depends on receptors and co-factors such as hACE2, TMPRSS2 and NRP1 (Martínez-Mármol et al, 2023a). Moreover, other viruses such as rabies virus, Japanese encephalitis virus, vesicular stomatitis virus, poliovirus, measles virus, herpes simplex virus, varicella-zoster virus, Zika virus, dengue virus, Nipah virus, chikungunya virus can cause syncytia to form in pulmonary and cardiac tissue (Martínez-Mármol et al, 2023b).…”

Section: Introductionmentioning

confidence: 99%

“…That process depends on receptors and co-factors such as hACE2, TMPRSS2 and NRP1 (Martínez-Mármol et al, 2023a). Moreover, other viruses such as rabies virus, Japanese encephalitis virus, vesicular stomatitis virus, poliovirus, measles virus, herpes simplex virus, varicella-zoster virus, Zika virus, dengue virus, Nipah virus, chikungunya virus can cause syncytia to form in pulmonary and cardiac tissue (Martínez-Mármol et al, 2023b). Viral infections may also lead to transcriptomic and structural changes in the host cells, such as the molecular signatures of brain aging and loss of cortical gray matter observed after severe COVID-19 infections (Douaud et al, 2022; Mavrikaki et al, 2022; Zhang et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

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Sex-Specific Development of ssRNA Virus Receptor Gene Expression in the Human Brain

Halabian,

Monteiro,

et al. 2023

Preprint

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Viral infection severity often varies with host factors such as age and sex. The pathogenesis of infections caused by a broad range of viruses, from neurotropic viruses like Rabies and Zika to respiratory viruses such as influenza and SARS-CoV-2, differ between the sexes and across the lifespan. Typically, older males are more susceptible to severe acute outcomes, while females are more vulnerable to the post-acute sequelae of infections. All of these complications can include neuroinflammation, stroke, cognitive dysfunction, and delirium. While these symptoms can be secondary to infection, recent studies suggest that even peripheral infections can lead to neuropathological changes in the brain. However, few studies have characterized the expression of viral receptors in the human brain or examined age- or sex-related differences in such expression. In this study, we used a publicly accessible transcriptomic database to assess the impact of age and sex on the expression of 67 viral host factor genes, associated with ten virus families. Analyzing data from 15 brain areas (n=33, F=14, M=19, age:4 mo-80 yrs), we determined the lifespan trajectory for each gene in each area via LOESS regressions. We used unsupervised hierarchical clustering to determine if a brain-wide pattern or virus family pattern can be detected. Using Dense-tSNE, a dimension-reduction and visualization technique, we discovered four distinct developmental trajectories, clustering the areas into two mixed-sex subcortical clusters and one each of male and female cortical clusters. Applying Differential Expression Sliding Window Analysis (DeSWAN), we identified the genes driving these age- and sex-related differences. Many sex differences were noted in childhood, potentially impacting the brain’s susceptibility to viral infections and underscoring a broader dimorphic organization of male and female brains. These insights contribute to our understanding of sex-specific responses to viral infections, offering the potential for more personalized treatment strategies.

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COVID‐19 and cognitive impairment: From evidence to SARS‐CoV‐2 mechanism

Pan,

Niu,

Feng

et al. 2024

Brain-X

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Caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), coronavirus disease 2019 (COVID‐19) primarily manifests as respiratory dysfunction. However, emerging evidence suggests SARS‐CoV‐2 can invade the brain, leading to cognitive impairment (CI). It may spread to other brain regions through transsynaptic neurons, including the olfactory, optic, and vagus nerves. Moreover, it may invade the central nervous system through blood transmission or the lymphatic system. This review summarizes the neuroimaging evidence from clinical and imaging studies of COVID‐19‐associated CIs, including magnetic resonance imaging and 18F‐fluorodeoxyglucose positron emission tomography‐computed tomography. The mechanisms underlying COVID‐19‐associated CIs are currently being actively investigated. They include nonimmune effects, such as viral proteins, tissue hypoxia, hypercoagulability, and pathological changes in neuronal cells, and immune effects, such as microglia and astrocyte activation, peripheral immune cell infiltration, blood‐brain barrier impairment, cytokine network dysregulation, and intestinal microbiota. Inflammation is the central feature. Both central and systemic inflammation may cause acute and persistent neurological changes, and existing evidence indicates that inflammation underlies the elevated risk of Alzheimer's disease. Finally, potential therapeutic options for COVID‐19‐associated CIs are discussed. In‐depth research into the pathological mechanisms is still needed to help develop new therapies.

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SARS-CoV-2 infection and viral fusogens cause neuronal and glial fusion that compromises neuronal activity

Cited by 31 publications

References 80 publications

Increased neurovirulence of omicron BA.5 and XBB variants over BA.1 in K18-hACE2 mice and human brain organoids

Increased neurovirulence of omicron BA.5 and XBB variants over BA.1 in K18-hACE2 mice and human brain organoids

Sex-Specific Development of ssRNA Virus Receptor Gene Expression in the Human Brain

COVID‐19 and cognitive impairment: From evidence to SARS‐CoV‐2 mechanism

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