Virus World

The cGAS-STING pathway appears to contribute to dysregulated inflammation during coronavirus disease 2019 (COVID-19); however, inflammatory factors related to long COVID are still being investigated. In the present study, we evaluated the association of cGAS and STING gene expression levels and plasma IFN-α, TNF-α and IL-6 levels with COVID-19 severity in acute infection and long COVID, based on analysis of blood samples from 148 individuals, 87 with acute COVID-19 and 61 in the post-COVID-19 period. Quantification of gene expression was performed by real-time PCR, and cytokine levels were quantified by ELISA and flow cytometry.

In acute COVID-19, cGAS, STING, IFN-α, TNF-α, and IL-6 levels were higher in patients with severe disease than in those with nonsevere manifestations (p < 0.05). Long COVID was associated with elevated cGAS, STING and IFN-α levels (p < 0.05). Activation of the cGAS-STING pathway may contribute to an intense systemic inflammatory state in severe COVID-19 and, after infection resolution, induce an autoinflammatory disease in some tissues, resulting in long COVID.

Published in Nature Scientific Reports (Feb. 29, 2024):

https://doi.org/10.1038/s41598-024-55696-0 

Conditioning the lungs with interferon-gamma, a natural immune system protein (cytokine) best known for fighting bacterial infections, appears to be a strong antiviral for SARS-CoV-2, according to National Institutes of Health scientists and colleagues. Their new study, published in Nature Communications, shows in two different mouse models that when a bacterial infection triggers the release of interferon-gamma in the lungs, those animals subsequently are protected from infection by SARS-CoV-2, the virus that causes COVID-19. The investigators further report that using recombinant interferon-gamma in the nose of study mice at the time of viral exposure substantially reduces SARS-CoV-2 infection and COVID disease....

Published in Nature Communications (Dec. 2023):

https://doi.org/10.1038/s41467-023-43447-0 

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA generally becomes undetectable in upper airways after a few days or weeks postinfection. Here we used a model of viral infection in macaques to address whether SARS-CoV-2 persists in the body and which mechanisms regulate its persistence. Replication-competent virus was detected in bronchioalveolar lavage (BAL) macrophages beyond 6 months postinfection. Viral propagation in BAL macrophages occurred from cell to cell and was inhibited by interferon-γ (IFN-γ). IFN-γ production was strongest in BAL NKG2r+CD8+ T cells and NKG2Alo natural killer (NK) cells and was further increased in NKG2Alo NK cells after spike protein stimulation. However, IFN-γ production was impaired in NK cells from macaques with persisting virus. Moreover, IFN-γ also enhanced the expression of major histocompatibility complex (MHC)-E on BAL macrophages, possibly inhibiting NK cell-mediated killing. Macaques with less persisting virus mounted adaptive NK cells that escaped the MHC-E-dependent inhibition. Our findings reveal an interplay between NK cells and macrophages that regulated SARS-CoV-2 persistence in macrophages and was mediated by IFN-γ. Huot et al. show that interferon-γ (IFN-γ) regulates the persistence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in bronchoalveolar macrophages from cynomolgus macaques up to 18 months postinfection.

Published in Nat. Immunology (Nov. 2, 2023):

https://doi.org/10.1038/s41590-023-01661-4 

Given early, one shot sliced hospitalization risk by half in large trial.  From the earliest days of the pandemic, scientists have hoped that interferons, a family of potent proteins that are the body’s own first line of defense against viruses, could become weapons against SARS-CoV-2. Because the virus effectively blunts the interferon response, researchers thought providing extra interferons could counter it. But for 2 years, interferons have disappointed in trials in hospitalized patients. Now, a strikingly positive result from a large trial of nonhospitalized, high-risk people in Brazil has revived hopes. In a study of more than 1900 people, those who received a single shot of a drug called peginterferon lambda within 7 days of developing symptoms of COVID-19 were half as likely to be hospitalized or to endure lengthy emergency room visits as those who received placebo. The effect, which the trial’s sponsor, Eiger BioPharmaceuticals, reported in a press release, was seen across many SARS-CoV-2 variants, including Omicron. Eiger said today it plans to apply for an emergency use authorization for the shot from the U.S. Food and Drug Administration by 30 June. It plans to make full data from the trial available at that time. “If what they said in the press release is true, it is a very good result,” says Ivan Zanoni, an immunologist at Harvard Medical School and Boston Children’s Hospital. But he is reserving judgment until a paper details the results, in part because a much smaller trial in younger outpatients with early, uncomplicated SARS-CoV-2 infection found the Eiger injection did not reduce symptom duration or the time it took people to clear the virus. The scientists who led that trial agree. “Until we see a peer-reviewed publication, I am cautious re[garding] press release[s] from companies,” Upinder Singh, an infectious diseases physician at the Stanford University School of Medicine, said in an email.

The caution may also reflect the discouraging results from trials of other kinds of interferons. Large trials sponsored by the National Institutes of Health, the World Health Organization, and the company Synairgen all treated hospitalized patients, and all failed. The current trial was set up to catch patients early. That’s because interferons act in the earliest hours and days after viral infection, kicking off a cascade of other proteins that attack the virus at every stage of its life cycle. Located at 12 sites in Brazil, the trial targeted nonhospitalized patients who were older than 50 and/or were at higher risk of severe COVID-19 because they had conditions including diabetes, obesity, high blood pressure, and lung disease. Eighty-four percent of participants were vaccinated. They received a single injection under the skin of placebo or peginterferon lambda, a drug Eiger was already developing to fight hepatitis D.  The company says 25 of 916 patients (2.7%) in the treatment arm were hospitalized or spent more than 6 hours in an emergency room, compared with 57 of 1020 patients (5.6%) who received placebo. Eiger also reported that only one person in the treatment group died, compared with four in the placebo group, although the number of deaths was too small to be statistically meaningful. “We believe we have a study that is highly generalizable to the current COVID environment in the U.S. and globally,” says Eiger CEO David Cory. He says that whereas the current leading antiviral, Pfizer’s Paxlovid, is given as a series of pills over 5 days, a single shallow injection of interferon—similar to those people with type 1 diabetes routinely self-administer—“has the potential to be a one-and-done therapy, especially for high-risk patients.”

Based on the press release, the results are “quite impressive,” says Andreas Wack, an immunologist at the Francis Crick Institute, who has studied the role of lambda interferons in COVID-19. “I’m very hopeful that this may go somewhere.” “From a basic science perspective, this is what was expected to happen,” Zanoni says. Lambda interferons are type 3 interferons, which have receptors mainly on epithelial surfaces, such as those lining the respiratory tract. The better known, type 1 interferons act on every cell in the body, increasing the likelihood of off-target effects. They also promote inflammation more than type 3 interferons—a decided risk in a disease that, later in its course, can tip patients into hyperinflammatory states. In mice inoculated with SARS-CoV-2, inhaled lambda interferon limited viral infection throughout the respiratory tract without causing excessive inflammation, a team based at Washington University School of Medicine in St. Louis reported in Cell Reports on 15 April. And when the same team engineered mice to lack a receptor specific to lambda interferon-1 (IFNL-1)—the protein in the Eiger product—their viral loads soared compared to mice with intact receptors. Last year, Zanoni, and colleagues analyzed lung fluid and throat and nose samples from COVID-19 patients. IFNL1 appeared to be associated with the most protective responses, keeping the virus corralled in the upper airways. “I was happy to see [Eiger’s apparently successful interferon] was lambda 1 because that would have been our prediction,” Zanoni says. Other scientists also note that the interferon response isn’t vulnerable to evolution of new, resistant SARS-CoV-2 variants, unlike monoclonal antibodies, vaccine-induced immunity, or, perhaps, antiviral pills such as Paxlovid. “This is a host-targeting drug versus a virus-targeting drug … so resistance is really less of an issue,” says Jordan Feld, a hepatologist at the University of Toronto. He ran a smaller trial of the Eiger drug in early-stage outpatients and found that a single injection sped clearance of the virus. (Feld has received consulting fees from Eiger.) Eleanor Fish, an immunologist at the University of Toronto who is an investigator on two unrelated trials of type 1 interferons wonders whether a small company can make enough product to make a difference. “The results are good. My question is: Do they have the capacity to actually make this available?” (The company says it expects to have 300,000 doses ready by the end of this year.) Feld, who treats patients at Toronto General Hospital, says if the data hold up, the Eiger drug’s all-purpose antiviral qualities could make it useful for future respiratory disease pandemics. “While you are waiting for the very specific targeted therapy … this is one to think about early because it’s very likely to have activity against most viruses.”

Published in Science (May 5, 2022):

https://doi.org/10.1126/science.adc8696 

Cells taken from patients at the time of diagnosis who later developed severe COVID-19 show a muted antiviral response, study finds. 

• Researchers studied cells collected by nasal swabs at the moment of diagnosis for both mild and severe COVID-19 patients
• Cells taken from patients who went on to develop severe disease had a muted antiviral response compared to those who went on to develop mild disease
• This suggests that it may be possible to develop early interventions that prevent severe COVID-19 from developing
• The team also identified infected host cells and pathways associated with protection against infection that may enable new therapeutic strategies for COVID-19 and other respiratory viral infections

Over the past 18 months, researchers have learned much about COVID-19 and its viral cause, SARS-CoV-2. They know how the virus enters the body, coming in through the nose and mouth and beginning its infection in the mucus layers of the nasal passageway. They know that infections that remain in the upper airway are likely to be mild or asymptomatic, while infections that progress down the airway to the lungs are much more severe and can lead to fatal disease. And they have identified common risk factors for severe disease, like age, gender, and obesity. But there are still many unanswered questions — such as when, and where, the course of severe COVID-19 is determined. Does the pathway to severe disease begin only after the body has failed to control mild disease, or could it start much earlier than that? Researchers at the Ragon Institute of MGH, MIT, and Harvard; the Broad Institute of MIT and Harvard; Boston Children’s Hospital (BCH); MIT; and the University of Mississippi Medical Center (UMMC) wondered whether this path towards severe disease could start much earlier than expected — perhaps even within the initial response created when the virus enters the nose.

To test this, they studied cells taken from nasal swabs of patients at the time of their initial COVID-19 diagnosis, comparing patients who went on to develop mild COVID-19 to those who progressed into more severe disease and eventually required respiratory support. Their results showed that patients who went on to develop severe COVID-19 exhibited a much more muted antiviral response in the cells collected from those early swabs, compared to patients who had a mild course of disease. The paper appears in the journal Cell.  “We wanted to understand if there were pronounced differences in samples taken early in the course of disease that were associated with different severities of COVID-19 as the disease progressed,” said co-senior author José Ordovás-Montañés, an associate member in the Klarman Cell Observatory at Broad and assistant professor at BCH and Harvard Medical School. “Our findings suggest that the course of severe COVID-19 may be determined by the body’s intrinsic antiviral response to initial infection, opening up new avenues for early interventions that could prevent severe disease.” To understand the early response to infection, Sarah Glover of the Division of Digestive Diseases at UMMC and her laboratory collected nasal swabs from 58 people. Thirty-five swabs came from COVID-19 patients, taken at the time of diagnosis, representing a variety of disease states from mild to severe. Seventeen swabs came from healthy volunteers and six came from patients with respiratory failure due to other causes. The team isolated individual cells from each sample and sequenced them, looking for RNA that would indicate what kind of proteins the cells were making — a proxy for understanding what a given cell is doing at the moment of collection. Cells use RNA as instructions to make proteins — tools, machinery, and building blocks used within and by the cell to perform different functions and respond to its environment. By studying the collection of RNA in a cell — its transcriptome — researchers understand how a cell is responding, at that particular moment in time, to environmental changes such as a viral infection. Researchers can even use the transcriptome to see if individual cells are infected by an RNA virus like SARS-CoV-2.

Alex Shalek, co-senior author on the study, a member of the Ragon Institute of MGH, MIT, and Harvard, and institute member at Broad, specializes in studying the transcriptomes of individual cells. His lab has helped develop innovative approaches to sequence thousands of single cells from low-input clinical samples, like the nasal swab of COVID-19 patients, and uses the resulting data to create high-resolution pictures of the body’s orchestrated response to infection at the sample site. “Our single-cell sequencing approaches allow us to comprehensively study the body’s response to disease at a specific moment in time,” said Shalek, who is also an associate professor at MIT in the Institute for Medical Engineering & Science, the Department of Chemistry, and the Koch Institute for Integrative Cancer Research. “This gives us the ability to systematically explore features that differentiate one course of disease from another as well as cells that are infected from those that are not. We can then leverage this information to guide the development of more effective preventions and cures for COVID-19 and other viral infections.”

Ordovás-Montañés’s lab studies inflammatory responses and their memory, specializing in those found in epithelial cells — the top layer of cells, like those that line your nasal passageways and are collected by nasal swabs. Working with the Shalek lab and that of Bruce Horwitz, a senior associate physician in the BCH Division of Emergency Medicine, the researchers interrogated how both epithelial and immune cells were responding to early COVID-19 infection from the single-cell transcriptome data. First, the team found that the antiviral response, driven by a family of proteins called interferons, was much more muted in patients who went on to develop severe COVID-19. Second, patients with severe COVID-19 had higher amounts of highly inflammatory macrophages, immune cells that contribute to high amounts of inflammation, often found in severe or fatal COVID-19. Since these samples were taken well before COVID-19 had reached its peak state of disease in the patients, both these findings indicate that the course of COVID-19 may be determined by the initial or very early response of the nasal epithelial and immune cells to the virus. The lack of strong initial antiviral response may allow the virus to spread more rapidly, increasing the chances that it can move from the upper to lower airways, while the recruitment of inflammatory immune cells could help drive the dangerous inflammation in severe disease. Finally, the team also identified infected host cells and pathways associated with protection against infection — cells and responses unique to patients that went on to develop a mild disease. These findings may allow researchers to discover new therapeutic strategies for COVID-19 and other respiratory viral infections. If, as the team’s evidence suggests, the early stages of infection can determine disease, it opens a path for scientists to develop early interventions that can help prevent severe COVID-19 from developing. The team’s work even identified potential markers of severe disease, genes that were expressed in mild COVID-19 but not in severe COVID-19.  “Nearly all our severe COVID-19 samples lacked expression of several genes we would typically expect to see in an antiviral response,” said Carly Ziegler, a graduate student in the Health Science and Technology program at MIT and Harvard and one of the study’s co-first authors. “If further studies support our findings, we could use the same nasal swabs we use to diagnose COVID-19 to identity potentially severe cases before severe disease develops, creating an opportunity for effective early intervention.”

Research Cited Published in Cell:

https://www.cell.com/cell/pdf/S0092-8674(21)00882-5.pdf 

Can prior exposure to other respiratory viruses like the common cold before infection by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pathogen responsible for the coronavirus disease 2019 (COVID-19), offer protection against COVID-19?  Researchers at the Yale School of Medicine found that rhinovirus, which is the virus that is most commonly responsible for the common cold, accelerates interferon-stimulated genes (ISG), which are early response molecules in the immune system. The increased expression of these genes was found to prevent SARS-CoV-2 replication within airway tissues that were previously infected with rhinovirus. The study, which was published in the Journal of Experimental Medicine, shed light on the use of interferons (IFNs), which are immune system proteins, in COVID-19 patients. The researchers also noted that IFN treatment could be used for prophylactic purposes in high-risk patients who have been exposed to SARS-CoV-2.

The study

The initial replication of SARS-CoV-2 in the upper respiratory tract is needed to establish infection. In SARS-CoV-2 infection, the virus enters lung cells through the angiotensin-converting enzyme 2 (ACE2) receptor. The cell-free and macrophage-phagocytosed virus can then spread to other organs and infect ACE2-expressing cells at local sites, which can cause multi-organ injury. Previous studies demonstrated that at the later stages of COVID-19, high IFN levels coincide with a more severe disease that is likely due to a hyperactive immune response. However, recent evidence has demonstrated that ISG instead offers protection during SARS-CoV-2 infection. This work was largely inspired by previous studies that found that common cold viruses may offer protection against the influenza virus. The researchers aimed to determine whether rhinoviruses would provide a similar beneficial effect against SARS-CoV-2.

Study findings

First, the team sought to capture early host-virus dynamics in the human nasopharynx using serial patient samples. Through the use of transcriptomics and biomarker-based tracking in these samples, the researchers observed a robust induction of ISG in the airway mucosa of these COVID-19 patients. Furthermore, ISG levels were found to align with viral load levels in these patients, with patients with the highest viral load tending to have higher ISG expression levels than those with the lowest viral loads. The researchers also studied the functional consequences of modulating the host innate immune response in primary human airway epithelial air-liquid interface organoid cultures. When the researchers infected lab-grown human airway tissue with SARS-CoV-2, they found that the viral load in the tissue doubled every six hours for the first three days. Meanwhile, the replication of SARS-CoV-2 was halted entirely in the tissue that was previously exposed to rhinovirus. When the antiviral defenses were blocked, SARS-CoV-2 successfully replicated in the tissues previously exposed to the common cold virus. The results showed that SARS-CoV-2 induces an IFN response in the nasopharynx across diverse patient groups. The same protective defenses were found to slow infection with SARS-CoV-2 even without prior exposure to rhinovirus.

Study takeaways

Taken together, the current study found that the defenses mediated by ISG at the time of SARS-CoV-2 exposure play an important role in determining infection severity. The heterologous antiviral response that is triggered by a different virus can therefore offer protection against SARS-CoV-2. The study findings also explain the phenomenon that occurs when common colds are frequent at certain times of the year, during which the rates of infections with other viruses like influenza tend to decrease. However, the researchers fear that such respiratory viruses can become stronger as a result of their dormancy over the past year due to social distancing measures. When these restrictions are eased, cases of common colds and other viral infections may arise. IFN treatment now holds promise as a preventive treatment for COVID-19. The researchers warned that the efficacy of this treatment approach will likely depend on the timing of its use. Based on theories, IFN treatment could be used as a prophylactic measure in high-risk patients. Currently, IFN treatments are being investigated in clinical trials, which have shown their beneficial use if given early in the course of the infection. In addition to vaccination efforts, finding a potential preventive measure for COVID-19 remains crucial as the world continues to grapple with this disease.

Original findings published in the Journal of Exp. Medicine (June 15, 2021):

This case series describes rare putative X-chromosomal loss-of-function variants associated with impaired peripheral mononuclear blood cell interferon signaling in 4 young male patients hospitalized with severe coronavirus disease 2019 (COVID-19) in the Netherlands. Severe coronavirus disease 2019 (COVID-19) can occur in younger, predominantly male, patients without preexisting medical conditions. Some individuals may have primary immunodeficiencies that predispose to severe infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To explore the presence of genetic variants associated with primary immunodeficiencies among young patients with COVID-19.

Case series of pairs of brothers without medical history meeting the selection criteria of young (age <35 years) brother pairs admitted to the intensive care unit (ICU) due to severe COVID-19. Four men from 2 unrelated families were admitted to the ICUs of 4 hospitals in the Netherlands between March 23 and April 12, 2020. The final date of follow-up was May 16, 2020. Available family members were included for genetic variant segregation analysis and as controls for functional experiments. Results of rapid clinical whole-exome sequencing, performed to identify a potential monogenic cause. Subsequently, basic genetic and immunological tests were performed in primary immune cells isolated from the patients and family members to characterize any immune defects.

The 4 male patients had a mean age of 26 years (range, 21-32), with no history of major chronic disease. They were previously well before developing respiratory insufficiency due to severe COVID-19, requiring mechanical ventilation in the ICU. The mean duration of ventilatory support was 10 days (range, 9-11); the mean duration of ICU stay was 13 days (range, 10-16). One patient died. Rapid clinical whole-exome sequencing of the patients and segregation in available family members identified loss-of-function variants of the X-chromosomal TLR7. In members of family 1, a maternally inherited 4-nucleotide deletion was identified (c.2129_2132del; p.[Gln710Argfs*18]); the affected members of family 2 carried a missense variant (c.2383G>T; p.[Val795Phe]). In primary peripheral blood mononuclear cells from the patients, downstream type I interferon (IFN) signaling was transcriptionally downregulated, as measured by significantly decreased mRNA expression of IRF7, IFNB1, and ISG15 on stimulation with the TLR7 agonist imiquimod as compared with family members and controls. The production of IFN-γ, a type II IFN, was decreased in patients in response to stimulation with imiquimod. In this case series of 4 young male patients with severe COVID-19, rare putative loss-of-function variants of X-chromosomal TLR7 were identified that were associated with impaired type I and II IFN responses. These preliminary findings provide insights into the pathogenesis of COVID-19.

Published in JAMA (July 24, 2020):

https://doi.org/10.1001/jama.2020.13719

All respiratory viruses establish primary infections in the nasal epithelium, where efficient innate immune induction may prevent dissemination to the lower airway and thus minimize pathogenesis. Human coronaviruses (HCoVs) cause a range of pathologies, but the host and viral determinants of disease during common cold versus lethal HCoV infections are poorly understood. We model the initial site of infection using primary nasal epithelial cells cultured at air-liquid interface (ALI).

HCoV-229E, HCoV-NL63 and human rhinovirus-16 are common cold-associated viruses that exhibit unique features in this model: early induction of antiviral interferon (IFN) signaling, IFN-mediated viral clearance, and preferential replication at nasal airway temperature (33°C) which confers muted host IFN responses. In contrast, lethal SARS-CoV-2 and MERS-CoV encode antagonist proteins that prevent IFN-mediated clearance in nasal cultures. Our study identifies features shared among common cold-associated viruses, highlighting nasal innate immune responses as predictive of infection outcomes and nasally-directed IFNs as potential therapeutics.

Preprint in bioRxiv (Dec.19, 2023):

https://doi.org/10.1101/2023.12.18.571720 

An ancient conflict between hosts and pathogens has driven the innate and adaptive arms of immunity. Knowledge about this interplay can not only help us identify biological mechanisms but also reveal pathogen vulnerabilities that can be leveraged therapeutically. The humoral response to SARS-CoV-2 infection has been the focus of intense research, and the role of the innate immune system has received significantly less attention. Here, we review current knowledge of the innate immune response to SARS-CoV-2 infection and the various means SARS-CoV-2 employs to evade innate defense systems. We also consider the role of innate immunity in SARS-CoV-2 vaccines and in the phenomenon of long COVID.

Published in Cell. Mol. Immunology (Nov. 20, 2023):

https://doi.org/10.1038/s41423-023-01104-y 

Significance

Abstract

Circulating autoantibodies (auto-Abs) neutralizing high concentrations (10 ng/mL, in plasma diluted 1 to 10) of IFN-α and/or -ω are found in about 10% of patients with critical COVID-19 pneumonia, but not in subjects with asymptomatic infections. We detect auto-Abs neutralizing 100-fold lower, more physiological, concentrations of IFN-α and/or -ω (100 pg/mL, in 1/10 dilutions of plasma) in 13.6% of 3,595 patients with critical COVID-19, including 21% of 374 patients > 80 years, and 6.5% of 522 patients with severe COVID-19. These antibodies are also detected in 18% of the 1,124 deceased patients (aged 20 days-99 years; mean: 70 years). Moreover, another 1.3% of patients with critical COVID-19 and 0.9% of the deceased patients have auto-Abs neutralizing high concentrations of IFN-β. We also show, in a sample of 34,159 uninfected subjects from the general population, that auto-Abs neutralizing high concentrations of IFN-α and/or -ω are present in 0.18% of individuals between 18 and 69 years, 1.1% between 70 and 79 years, and 3.4% >80 years. Moreover, the proportion of subjects carrying auto-Abs neutralizing lower concentrations is greater in a subsample of 10,778 uninfected individuals: 1% of individuals <70 years, 2.3% between 70 and 80 years, and 6.3% >80 years. By contrast, auto-Abs neutralizing IFN-β do not become more frequent with age. Auto-Abs neutralizing type I IFNs predate SARS-CoV-2 infection and sharply increase in prevalence after the age of 70 years. They account for about 20% of both critical COVID-19 cases in the over-80s, and total fatal COVID-19 cases.

Published in Science Immunology (Aug.19, 2021):

https://doi.org/10.1126/sciimmunol.abl4340

The Ebola Virus Disease (EVD) is a rare and deadly disease in people and nonhuman primates. The viruses that cause EVD are located mainly in sub-Saharan Africa. People can get EVD through direct contact with an infected animal (bat or nonhuman primate) or a sick or dead person infected with Ebola virus. The virus is extremely skilled at escaping the immune system’s defenses. However, new hope comes from a study by Mount Sinai researchers, who report they have uncovered the complex cellular mechanisms of Ebola virus. Their research may help to identify potential pathways to treatment and prevention. The findings are published in the journal mBio, “Expression of the Ebola Virus VP24 Protein Compromises the Integrity of the Nuclear Envelope and Induces a Laminopathy-Like Cellular Phenotype.”  “Ebola virus (EBOV) VP24 protein is a nucleocapsid-associated protein that inhibits interferon (IFN) gene expression and counteracts the IFN-mediated antiviral response, preventing nuclear import of signal transducer and activator of transcription 1 (STAT1),” wrote the researchers. “Proteomic studies to identify additional EBOV VP24 partners have pointed to the nuclear membrane component emerin as a potential element of the VP24 cellular interactome. Here, we have further studied this interaction and its impact on cell biology. We demonstrate that VP24 interacts with emerin but also with other components of the inner nuclear membrane, such as lamin A/C and lamin B.” The team reported “how a protein of the Ebola virus, VP24, interacts with the double-layered membrane of the cell nucleus (known as the nuclear envelope), leading to significant damage to cells along with virus replication and the propagation of disease.”

“The Ebola virus is extremely skilled at dodging the body’s immune defenses, and in our study we characterize an important way in which that evasion occurs through disruption of the nuclear envelope, mediated by the VP24 protein,” said co-senior author Adolfo García-Sastre, PhD, professor of microbiology, and director of the Global Health and Emerging Pathogens Institute of the Icahn School of Medicine at Mount Sinai. “That disruption is quite dramatic and replicates rare, genetic diseases known as laminopathies, which can result in severe muscular, cardiovascular, and neuronal complications.” The researchers collaborated with research partners from CIMUS at the Universidad de Santiago de Compostela in Spain, and the Bernhard Nocht Institute for Tropical Medicine in Hamburg, Germany. Together, they identified the cellular membrane components that interact with VP24 to prompt nuclear membrane disruption.  The researchers demonstrated that VP24 disrupts signaling pathways that are meant to activate the immune system’s defenses against viruses. “We believe our discovery of the novel activities of the Ebola VP24 protein and the severe damage it causes to infected cells will help to promote further research into effective ways to treat and prevent the spread of deadly viruses, perhaps through a new inhibitor,” added García-Sastre. “Indeed, that research will hopefully identify even more precisely the molecular mechanisms by which viruses like Ebola invade the body and find ways to cleverly avoid its immune defenses.”

Published in mBio (July 6, 2021):

 https://doi.org/10.1128/mBio.00972-21