Virus World

Respiratory virus infections in humans cause a broad-spectrum of diseases that result in substantial morbidity and mortality annually worldwide. To reduce the global burden of respiratory viral diseases, preventative and therapeutic interventions that are accessible and effective are urgently needed, especially in countries that are disproportionately affected. Repurposing generic medicine has the potential to bring new treatments for infectious diseases to patients efficiently and equitably. In this study, we found that intranasal delivery of neomycin, a generic aminoglycoside antibiotic, induces the expression of interferon-stimulated genes (ISGs) in the nasal mucosa that is independent of the commensal microbiota.

Prophylactic or therapeutic administration of neomycin provided significant protection against upper respiratory infection and lethal disease in a mouse model of COVID-19. Furthermore, neomycin treatment protected Mx1 congenic mice from upper and lower respiratory infections with a highly virulent strain of influenza A virus. In Syrian hamsters, neomycin treatment potently mitigated contact transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In healthy humans, intranasal application of neomycin-containing Neosporin ointment was well tolerated and effective at inducing ISG expression in the nose in a subset of participants. These findings suggest that neomycin has the potential to be harnessed as a host-directed antiviral strategy for the prevention and treatment of respiratory viral infections.

Published in PNAS (April 22, 2024):

https://doi.org/10.1073/pnas.2319566121

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 

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 

Significance

Abstract

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  

The Drug Controller General of India (DCGI) on Friday granted emergency use approval for pharma major Zydus Cadila’s antiviral drug ‘Virafin’, to treat moderate COVID-19 disease in adults, company press release said. “A single dose subcutaneous regimen of the antiviral Virafin [a pegylated interferon alpha-2b (PegIFN)] will make the treatment more convenient for the patients. When administered early on during COVID, Virafin will help patients recover faster and avoid much of the complications. Virafin will be available on the prescription of a medical specialist for use in hospital/institutional setup,” the release added.  The drug’s safety profile is already well known as it is used in treating people with chronic hepatitis B and C. The drug has been repurposed for treating moderate COVID-19 disease. According to Dr. Sharvil Patel, Managing Director, Cadila Healthcare Limited, the therapy “significantly reduces viral load when given early on and can help in better disease management”.

In a multi-centre trial in 20-25 centres across India, the company found the drug reduced the need for supplemental oxygen. This clearly “indicates that the antiviral was able to control respiratory distress and failure which has been one of the major challenges in treating COVID-19”, the company said. In the phase-3 trials, the drug was able to achieve “better clinical improvement in the patients suffering from COVID-19”. A “higher proportion (91.15%) of patients administered the drug were RT-PCR negative by day seven as it ensures faster viral clearance”. According to an April 5 company press release, the drug reduced the duration for supplemental oxygen to 56 hours from 84 hours in moderate COVID-19 patients. The results of the phase-2 trial using the drug published in the International Journal of Infectious Diseases found that of the 20 participants who received the drug and standard of care, 19 (95%) achieved clinical improvement on day 15 compared to 13 of the 20 (68.42%) participants who were in the control arm and received only standard of care. The trial found that 80% and 95% of participants who received the therapy plus standard of care were RT-PCR negative on day seven and 14, respectively, compared to 63% and 68% in the control arm.

The significant improvement in clinical status on day 15 is likely due to faster viral reduction compared to the control arm. Participants with moderate disease showed a difference as early as day seven, which became significant by day 14, the authors say in the paper. Mild adverse events were reported in 11 participants in the phase-2 trial compared with eight in the control arm. According to the release, type I interferons are the body’s first line of defence against many viral infections. In old people, the ability to produce interferon alpha in response to viral infections gets reduced, which might be the reason for higher mortality. The drug when administered early during the disease can replace this deficiency and help in the recovery process.

Some of the severe respiratory symptoms of COVID-19 seem to result from the activity of specific immune cells, which can cause long-term inflammation of the lungs. Alexander Misharin at Northwestern University in Evanston, Illinois, and his colleagues examined fluid from the lungs of 88 people with severe pneumonia caused by SARS-CoV-2 infection (R. A. Grant et al. Nature https://doi.org/fqds; 2021). Most of these individuals had high numbers of a certain type of T cell, a class of immune cells, in their lungs. The researchers also found that nearly 70% of alveolar macrophages, a type of immune cell that is located in the tiny air sacs of the lungs, contained SARS-CoV-2. The cells harbouring the virus showed relatively high expression of genes involved in inflammation. The findings suggest that, once the virus reaches the lungs, it can infect macrophages, which respond by producing inflammatory molecules that attract T cells. T cells, in turn, produce a protein that stimulates macrophages to make more inflammatory molecules. This persistent lung inflammation could lead to some of the life-threatening consequences of SARS-CoV-2 infection.

Findings Published in Nature (Jan. 11, 2021):

https://doi.org/10.1038/s41586-020-03148-w 

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the ongoing coronavirus disease 19 (COVID-19) pandemic. Despite the urgent need, we still do not fully understand the molecular basis of SARS-CoV-2 pathogenesis and its ability to antagonize innate immune responses. Here, we use RNA-sequencing and ribosome profiling along SARS-CoV-2 infection and comprehensively define the mechanisms that are utilized by SARS-CoV-2 to shutoff cellular protein synthesis. We show SARS-CoV-2 infection leads to a global reduction in translation but that viral transcripts are not preferentially translated.

Instead, we reveal that infection leads to accelerated degradation of cytosolic cellular mRNAs which facilitates viral takeover of the mRNA pool in infected cells. Moreover, we show that the translation of transcripts whose expression is induced in response to infection, including innate immune genes, is impaired, implying infection prevents newly transcribed cellular mRNAs from accessing the ribosomes. Overall, our results uncover the multipronged strategy employed by SARS-CoV-2 to commandeer the translation machinery and to suppress host defenses.

Available as preprint in bioRxiv (November 25, 2020):

https://doi.org/10.1101/2020.11.25.398578 

Effective antiviral therapy is important for tackling the coronavirus disease 2019 (COVID-19) pandemic. We assessed the efficacy and safety of combined interferon beta-1b, lopinavir–ritonavir, and ribavirin for treating patients with COVID-19.

This was a multicentre, prospective, open-label, randomised, phase 2 trial in adults with COVID-19 who were admitted to six hospitals in Hong Kong. Patients were randomly assigned (2:1) to a 14-day combination of lopinavir 400 mg and ritonavir 100 mg every 12 h, ribavirin 400 mg every 12 h, and three doses of 8 million international units of interferon beta-1b on alternate days (combination group) or to 14 days of lopinavir 400 mg and ritonavir 100 mg every 12 h (control group). The primary endpoint was the time to providing a nasopharyngeal swab negative for severe acute respiratory syndrome coronavirus 2 RT-PCR, and was done in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT04276688.

Between Feb 10 and March 20, 2020, 127 patients were recruited; 86 were randomly assigned to the combination group and 41 were assigned to the control group. The median number of days from symptom onset to start of study treatment was 5 days (IQR 3–7). The combination group had a significantly shorter median time from start of study treatment to negative nasopharyngeal swab (7 days [IQR 5–11]) than the control group (12 days [8–15]; hazard ratio 4·37 [95% CI 1·86–10·24], p=0·0010). Adverse events included self-limited nausea and diarrhoea with no difference between the two groups. One patient in the control group discontinued lopinavir–ritonavir because of biochemical hepatitis. No patients died during the study.

Early triple antiviral therapy was safe and superior to lopinavir–ritonavir alone in alleviating symptoms and shortening the duration of viral shedding and hospital stay in patients with mild to moderate COVID-19. Future clinical study of a double antiviral therapy with interferon beta-1b as a backbone is warranted.

Published in The Lancet (May 8, 2020):

https://doi.org/10.1016/ S0140-6736(20)31042-4

Spring Bank Pharmaceuticals is stopping work on an experimental treatment for hepatitis B virus after serious side effects, including one patient death, were reported in a mid-stage study. The Spring Bank (NASDAQ: SBPH) drug, inarigivir soproxil, was the company’s lead therapeutic candidate. No details were released about the side effects observed in the clinical trial. Hopkinton, MA-based Spring Bank said Wednesday that it will work with outside experts and clinical trial investigators to care for the patients in the Phase 2b study, and to better understand what happened. Going forward, the company plans to focus on its immuno-oncology and inflammation research. Spring Bank’s stock price slid more than 23 percent to $1.30 per share after the news was announced Wednesday morning.

Inarigivir was designed to selectively activate a protein in liver cells called retinoic acid-inducible gene 1. This approach was hoped to block replication of the hepatitis B virus and kick off the interferon signaling pathways that are part of the body’s antiviral defense. The company also hoped that this dual mechanism would make it attractive as part of a combination treatment with other hepatitis B therapies. Spring Bank had tested inarigivir in partnership with Gilead Sciences (NASDAQ: GILD). Separate Phase 2 studies evaluated a 200 mg dose of that drug in combination with Gilead’s tenofovir disoproxil fumarate (Viread) and tenofovir alafenamide (Vemlidy). Spring Bank says the patient death occurred in a Phase 2 study that tested a 400 mg dose of inarigivir by itself after patients stopped treatment with other antiviral therapies. With its lead hepatitis B drug now sidelined, Spring Bank will turn its attention to cancer and inflammatory drugs developed with its stimulator of interferon genes (STING) agonist platform. The most advanced of those drug candidates, SB 11285, is currently in a Phase 1a/1b study testing it in cancer. In a prepared statement, Spring Bank president and CEO Martin Driscoll said that he hopes to have enough data by the end of this year to support advancing that drug to Phase 2...

Antibiotics can leave the lung vulnerable to flu viruses, leading to significantly worse infections and symptoms, finds a new study in mice.

The research discovered that signals from gut bacteria help to maintain a first line of defence in the lining of the lung. When mice with healthy gut bacteria were infected with the flu, around 80% of them survived. However, only a third survived if they were given antibiotics before being infected.

"We found that antibiotics can wipe out early flu resistance, adding further evidence that they should not be taken or prescribed lightly," explains Dr Andreas Wack, who led the research at the Francis Crick Institute. "Inappropriate use not only promotes antibiotic resistance and kills helpful gut bacteria, but may also leave us more vulnerable to viruses. This could be relevant not only in humans but also livestock animals, as many farms around the world use antibiotics prophylactically. Further research in these environments is urgently needed to see whether this makes them more susceptible to viral infections."

To test whether the protective effect was related to gut bacteria rather than local processes in the lung, the researchers treated mice with antibiotics and then repopulated their gut bacteria through faecal transplant. This restored interferon signalling and associated flu resistance, suggesting that gut bacteria play a crucial role in maintaining defences.

These studies were published in Cell Reports:

 https://doi.org/10.1016/j.celrep.2019.05.105

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 

Highlights

Summary

Immune genes could play a part in the risk of needing intensive care when infected with SARS-CoV-2. An analysis of DNA from more than 24,000 people who had COVID-19 and required treatment in intensive care has yielded more than a dozen new genetic links to the risk of developing extreme illness from the disease. The study, which was published on 17 May in Nature1 and has more than 2,000 authors, highlights the role of the immune system in fuelling the later stages of particularly severe COVID-19. The results could one day contribute to the development of therapies for COVID-19 — and potentially other diseases that cause acute respiratory distress or sepsis. “These are likely to be processes that are active in other conditions,” says Kenneth Baillie, an intensive-care specialist at the University of Edinburgh, UK, and lead author on the study. “Everything that we’ve done in COVID will, I think, be relevant to other groups of patients that we haven’t identified yet.”

Team effort

Much of the data were collected from people who were infected with SARS-CoV-2 during the first waves of the pandemic in the United Kingdom. At that time, many intensive-care staff members were terrified of spending time on the ward, says Baillie. A coronavirus outbreak in 2003 caused by the related virus SARS-CoV had a mortality rate of about 10% and had hit health-care workers particularly hard. “We were nervous,” says Baillie. “Certainly, in the first wave of the pandemic, and for some people in subsequent waves, it seemed like a considerable personal risk.” Despite their fear and the frenzy of providing care at the onset of the pandemic, scores of health-care workers took on the added burden of enrolling participants in studies that investigate how genetics might have contributed to disease severity. Many of the participants were on ventilators, and enrolling them meant long discussions with relatives who were going through some of the most difficult times of their lives, says Baillie. The result was an effort called GenOMICC, which researchers hope will help to improve treatment options for COVID-19 and other conditions in future pandemics. Baillie and his colleagues analysed data from more than 24,000 people and combined this information with data sets from around the world. They found 49 DNA sequences that are associated with becoming critically ill from COVID-19. Sixteen of these had not been reported previously. Among these sequences are some that could affect the activity of genes and proteins involved in the immune system. Raging immune cells have long been implicated in causing some of the tissue damage seen in late-stage, severe cases of COVID-19. Baillie and his colleagues found genetic links to inflammatory responses and the activation of immune cells — processes that can damage the lungs and reduce their capacity to send oxygen to the body’s tissues. “It definitely expands our understanding of the genetic determinants of severe COVID,” says Brent Richards, a human geneticist at McGill University in Montreal, Canada. Richards is an investigator on another project called the COVID-19 Host Genetics Initiative, a global effort in which scientists from more than 54 countries share data. The diversity of that effort will provide a crucial counterpart to the GenOMICC study, which is predominantly drawn from participants of European descent, says Richards.

Reliable results

In addition to the new findings, it is important that the UK study has replicated many of the findings by other groups, says Alexander Hoischen, a geneticist at Radboud University Medical Center in Nijmegen, the Netherlands. Replication of results across different data sets is crucial when trying to tease apart the possible contribution of common genetic variants to disease. Even so, it will take a great deal of work to show that these variants contribute directly to critical illness — a necessary step to turn these initial findings into new therapies. “That is still a long trajectory,” says Hoischen. But putting together these large consortia of investigators and taking the first steps are considerable triumphs, he adds. In the early days of the pandemic, it was unclear how participation in such large endeavours would benefit the careers of individual scientists. “Many of them acted as purely human beings,” he says, instead of worrying about their careers. “It illustrates the degree of solidarity that we really witnessed in COVID times.”

Cited research published in Nature (May 17, 2023):

https://doi.org/10.1038/s41586-023-06034-3 

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 

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):

The emergence of SARS-CoV-2 variants with enhanced transmissibility, pathogenesis and resistance to vaccines presents urgent challenges for curbing the COVID-19 pandemic. While Spike mutations that enhance virus infectivity may drive the emergence of these novel variants, studies documenting a critical a role for interferon responses in the early control of SARS-CoV-2 infection, combined with the presence of viral genes that limit these responses, suggest that interferons may also influence SARS-CoV-2 evolution. Here, we compared the potency of 17 different human interferons against 5 viral lineages sampled during the course of the global outbreak that included ancestral and emerging variants. Our data revealed increased interferon resistance in emerging SARS-CoV-2 variants, indicating that evasion of innate immunity is a significant driving force for SARS-CoV-2 evolution. These findings have implications for the increased lethality of emerging variants and highlight the interferon subtypes that may be most successful in the treatment of early infections.

Posted in bioRxiv (March 21, 2021):

 https://doi.org/10.1101/2021.03.20.436257 

• Five genes seem to be associated with life-threatening cases of COVID-19, a new study found.
• The finding offers a potential explanation for why some patients get severely sick while others don't
• Two of these genes are linked to the innate immune response, while three are tied to inflammation and lung damage.
• The study offers a direction for more research into certain potential COVID-19 treatments.

A growing body of research is highlighting a select set of genes that may explain why some people develop more severe COVID-19 cases than others. Certain genes, for instance, instruct the body to make more ACE2 receptors, which the coronavirus uses to invade our cells. Studies show that people whose bodies naturally code for more of these receptors could be at higher risk of severe infection. On Friday, researchers at the University of Edinburgh announced that they'd identified five genes that may be associated with life-threatening cases of COVID-19. The genes are, perhaps unsurprisingly, associated with a weaker innate immune response and more aggressive inflammation. The new study compared more than 2,200 coronavirus patients in UK intensive-care units to patients of similar ancestry who hadn't tested positive for COVID-19.  The critically ill COVID-19 patients were found to have a lower expression of IFNAR2, a gene that helps code for proteins called interferons. These act as an emergency flare to warn the immune system of an intruder. The patients also displayed a variation in a cluster of genes called OAS, which normally helps prevent a virus from replicating.  What's more, the critically ill patients had higher expressions of the genes TYK2 and CCR2, which can drive inflammation and potentially lead to lung injury. And they displayed a variation in the gene DPP9, which scientists have linked to pulmonary fibrosis (damaged or scarred lung tissue).

A weak immune system is at risk of collapse

Typically, when our immune system senses a foreign invader, it dispatches white blood cells to destroy the threat. But in some patients, that innate immune response isn't strong enough to vanquish the coronavirus right away. This can trigger aggressive inflammation that damages healthy tissue or leads to organ failure. Dr. Panagis Galiatsatos, a pulmonary physician at Johns Hopkins Bayview Medical Center, compared that process to an earthquake — generally, it's the falling buildings that kill someone, not the quake itself. "Your infection is a rattling of your immune system," he previously told Business Insider. "If your immune system is just not well structured, it's just going to collapse." That means genetic signals that inhibit the body's natural defenses or encourage inflammation might set off a chain reaction that ultimately leads to critical respiratory failure. Other factors, including age and underlying health conditions, play a role in severe COVID-19 cases as well.

Implications for COVID-19 treatments

In unlocking some of the mysteries surrounding severe COVID-19, the Edinburgh researchers also found clues about how to treat patients. "Our results immediately highlight which drugs should be at the top of the list for clinical testing," Kenneth Baillie, an academic consultant in critical-care medicine who co-led the research, told Reuters.   Drugs that boost the expression of INFAR2, for instance, might help patients fight the virus before it wreaks havoc in the body. One potential treatment, a multiple sclerosis drug called Rebif, is attempting a similar approach by giving patients a boost of interferon. Merck, the company behind the drug, hopes the therapy might prevent the coronavirus from replicating. The Edinburgh study also suggests that drugs targeting inflammation could play a key role in halting the disease's progression. In particular, the researchers point to a class of anti-inflammatory drugs called Janus kinase (JAK) inhibitors, which are already used to treat rheumatoid arthritis.  One such arthritis drug, Eli Lilly's baricitinib, was recently authorized by the FDA for use in combination with remdesivir....

Cited Research Published in Nature (Dec. 11, 2020):

https://doi.org/10.1038/s41586-020-03065-y

Background

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

The new coronavirus may be using part of our immune system against us.The novel coronavirus is known to use a keyhole called the ACE2 receptor to "unlock" a cell and get inside, where it replicates and wreaks havoc. Now, researchers have found that the gene that encodes the ACE2 receptor may be stimulated by interferons, one of the body's main defenses against viruses. When a foreign pathogen invades, interferons act like "first responders"; the immune system releases these proteins to alert other cells that there's a pathogen in the body. But when interferons rush to alert the body to the coronavirus, they're actually stimulating the gene that ramps up expression of ACE2 receptors, which may lead to more ACE2 production and allow SARS-CoV-2 to infect even more cells.....

This finding is important, given that interferons are being tested as a possible treatment for the new coronavirus. However, it's still unclear whether an interferon treatment would help or harm patients. "It might be that in some patients, because of the timing or the dose, interferon can contain the virus, while in others, interferon promotes more infection," Ordovas-Montanes said in a statement. "We want to better understand where the balance lies and how we can maintain a productive antiviral response without producing more target cells for the virus to infect."...

Original report to be published in Cell:

https://doi.org/10.1016/j.cell.2020.04.035

https://www.cell.com/pb-assets/products/coronavirus/CELL_CELL-D-20-00767.pdf

The highly contagious norovirus causes diarrhea and vomiting and is notorious for spreading rapidly through densely populated spaces, such as cruise ships, nursing homes, schools and day care centers. Each year, it is responsible for some 200,000 deaths, mostly in the developing world. There are no treatments for this intestinal virus, often incorrectly referred to as stomach flu. Now, a new study led by scientists at Washington University School of Medicine in St. Louis has shown that gut microbes can tamp down or boost the severity of norovirus infection based on where along the intestine the virus takes hold.  The study, published Nov. 25 in the journal Nature Microbiology, suggests new routes to possible therapies for norovirus infection. Collaborators included researchers at the University of Florida, the University of Michigan and Yale University Medical School.

"There are currently no treatments for norovirus, which is very easily spread through fecal-oral transmission," said co-senior author Megan T. Baldridge, MD, Ph.D., an assistant professor of medicine at Washington University. "Norovirus is especially dangerous in young children, older adults and people with compromised immune systems. We are trying to understand how the gut microbes interact with norovirus in an effort to pursue new therapeutic strategies." In these mouse studies, the researchers found that normal gut bacteria boosted the severity of viral infection in the lower small intestine, which is in line with past work in the field. But simultaneously, normal gut bacteria blocked or inhibited viral infection in the upper small intestine. In other words, gut microbes can have totally opposite effects on norovirus infection depending on the infection's location along the length of the gut. "These results were a huge surprise to us," Baldridge said. "We showed that different parts of the intestine can show dramatically different responses to this type of infection. Our research reveals that we can't view the gut as a homogeneous tube that responds to infection in a uniform way."

Baldridge and her colleagues found that the difference in response was driven by bile acids, which are mainly known for their roles in digestion. "Bile acids are powerfully regulated by bacteria all along the gut," Baldridge said. "But there had not been a realization that these bile acids could prime the gut to mount an immune response against intestinal viruses." In the new study, the researchers showed that bile acids in the upper small intestine—but not the lower—stimulated the immune system to respond to the infection. The researchers determined that bile acids in that region of the gut triggered a molecule called interferon III—one of the body's key antiviral defenses in the intestine—to become activated. Baldridge noted that this complexity of interactions between gut microbes and bile acids could explain some of the variability seen in norovirus infections. Some people become extremely ill with this virus; others develop no symptoms at all. "The different ways people respond to viral infections could be related to their individual gut microbial community," Baldridge said. "The severity of an infection could be tied to where exactly along the gut you get an infection, and that might be controlled by your individual microbiome. Subtle differences along the intestine could end up having dramatic effects on how the gut perceives the virus and responds to it."...

Published in Nature Microbiology (25 November 2019):

https://nature.com/articles/s41564-019-0602-7