A drug treatment that acts as a decoy against SARS-CoV-2 was highly effective at preventing death and lung damage in humanized animal models of severe COVID-19 disease, according to a Nature Chemical Biology study from researchers at the University of Illinois Chicago. The study suggests that the drug has the potential to treat COVID-19 patients, including those who are infected with aggressive SARS-CoV-2 variants.
The study's senior lead author is Asrar Malik, professor in the department of pharmacology and regenerative medicine at the UIC College of Medicine. Jalees Rehman, professor in the department of pharmacology and regenerative medicine and the department of medicine, is a co-lead author of the study, "Engineered ACE2 decoy mitigates lung injury and death induced by SARS-CoV-2 variants."
"While vaccines remain the best option for preventing infections, long-term complications and death from COVID-19, there is an urgent need for the development of effective treatments for vulnerable patients, especially as new variants continue to arise," Rehman said.
"Vulnerable individuals who are at risk of developing severe COVID-19 include those who are unvaccinated or immunocompromised and therefore their immune system cannot protect them as well even after receiving vaccinations and boosters," he said. "In addition, new variants of SARS-CoV-2, such as the most recent omicron variant, may partially evade the immune system and can cause breakthrough infections. For all the vulnerable patients, we need to create an array of treatments so that health care providers can choose the most appropriate drug or combination of drugs, depending on the individual patient's disease stage and severity."
The drug treatment, developed through a partnership between UIC and the University of Illinois Urbana-Champaign, consists of an artificially engineered ACE2 protein designed with unprecedently high binding capacity for the spike protein of SARS-CoV-2, which binds to natural ACE2 protein receptors located on human cells and causes COVID-19. The drug works by competing for the spike protein and soaking up viruses before they can bind and enter cells.
In animal studies of severe COVID-19, the researchers used mouse models designed to carry the human ACE2 protein. With multiple treatment regimens, infected mice were given the drug intravenously. The researchers found that mice receiving the treatment showed markedly reduced death and no significant evidence of severe acute respiratory syndrome, the hallmark of the disease and primary cause of death. The mice receiving the drug also regained appetite and weight, which are signs of recovery.
The benefits were seen even when mice were exposed to the aggressive gamma variant, suggesting the drug's broad applicability against newly emerging COVID-19 variants.
"The reduced rates of fluid buildup in the lungs and of death in treatment group illustrates the potential of the ACE2 decoy to help people with severe COVID-19," Malik said. Severe fluid buildup in the lung is one of the complications of COVID-19 that makes it difficult for patients to breathe and leads to the need for a ventilator.
In additional studies, the researchers tested how well the decoy would bind and neutralize multiple variants of SARS-CoV-2. They observed that the decoy was able to bind to the spike proteins from all the variants tested, which included the alpha, beta, gamma, delta and epsilon variants, which were available at the time of the study. They also found that it bound equally, if not better, to the variants than it did to the original strain of the virus.
"Considering the emergence of omicron, it is very good news that the ACE2 decoy was able to bind and neutralize several variants, and this reinforces the potential of this drug as a treatment, including against new or future variants of the virus," Rehman said.
One of the exciting things about the drug, Rehman said, is that it has the potential to be used in combination with other drugs, especially those that prevent replication of the virus that has already entered cells or drugs that prevent an excessive immune response, which itself can worsen COVID-19 complications.
The researchers also found that the decoy protein could be delivered by inhalation directly to the lungs of mice.
Even though many of the treated animals recovered, a few mice developed lung scarring over time. According to the researchers, this highlights the importance of also studying and developing therapies for long-term COVID-19 complications, such as long COVID.
The research was funded in part by grants from the National Institutes of Health (P01HL060678, P01HL151327, R01HL154538, R01HL152515. R43AI162329, R01HL157489, T32HL007829).
UIC's Lianghui Zhang, assistant professor in the department of pharmacology and regenerative medicine, and UIUC's Erik Procko, associate professor in the department of biochemistry, are also co-lead authors of the study.
Additional co-authors of the paper are Shiqin Xiong, Matthew Lindeblad, Laura Cooper, Lijun Rong, Anthony Gugliuzza, Soumajit Dutta, Matthew Chan, Timothy Fan, Keith Bailey, Diwakar Shukla and Kui Chan.
Lianghui Zhang, Soumajit Dutta, Shiqin Xiong, Matthew Chan, Kui K. Chan, Timothy M. Fan, Keith L. Bailey, Matthew Lindeblad, Laura M. Cooper, Lijun Rong, Anthony F. Gugliuzza, Diwakar Shukla, Erik Procko, Jalees Rehman, Asrar B. Malik. Engineered ACE2 decoy mitigates lung injury and death induced by SARS-CoV-2 variants. Nature Chemical Biology, 2022; DOI: 10.1038/s41589-021-00965-6
Faulty DNA damage repair can lead to many types of cancer, neurodegenerative diseases, and other serious disorders. Investigators have developed high-throughput microscopy and machine learning systems that can identify and classify DNA repair factors. The investigators have identified nine previously unknown factors involved in the process of cellular DNA repair.
The DNA that lies tightly coiled in nearly every human cell is subjected to thousands of insults and injuries from within and without daily, which is why the human body has evolved multiple highly effective mechanisms for repairing DNA damage.
"We have in place exquisite mechanisms to repair DNA breaks, and when those fail, we end up with disease. We accumulate genomic instability, we accumulate mutations, and many diseases happen because of the inability of cells to repair DNA," says Raul Mostoslavsky, MD, PhD, scientific co-director of the MGH Cancer Center and the Laurel Schwartz Professor of Oncology (Medicine) at Harvard Medical School.
DNA damage repair is a double-edged sword: When it goes awry, it can lead to diseases such as cancer and degenerative motor disorders, but it can also be exploited to treat many forms of cancer using drugs that interfere with DNA's ability to fix itself, thereby causing cancerous cells to stop replicating and die.
Previous studies of DNA repair mechanisms were performed using systems developed by biochemists to purify proteins, but these systems have relatively low yields or "throughput," Mostoslavsky explains.
"We decided to develop a high-throughput assay to try to identify repair factors in a more unbiased way. We ended up developing a unique microscope-based automatic system to generate DNA damage and to collect information on proteins that are recruited to these types of damage," he says.
With co-investigators at the National Cancer Research Center in Madrid and at other centers in the U.S., Canada and China, Mostoslavsky and colleagues at MGH and Harvard have developed a highly sensitive method for visualizing DNA repair mechanisms at work. Using the technique, they have identified nine new proteins that are involved in DNA repair, a finding that can help researchers develop new cancer drugs, as well as methods for improving the effectiveness of existing therapies.
They describe their technique -- a combination of high-throughput microscopy and machine learning -- in the journal Cell Reports.
The investigators first developed a high-throughput microscopy test to analyze how proteins are attracted to or excluded from double-strand DNA breaks. With this system they generated a library of 384 mostly unknown factors and were able to identify which of these proteins are called into action when DNA damage occurs.
They then performed a proof-of-principle study, following one specific factor labeled PHF20 that is kept away from the site of DNA damage, and discovered that PHF20 is excluded because it can interfere with recruitment of another critical DNA repair factor labeled 53BP1.
The systems Mostoslavsky and colleagues developed could, for example, help improve the treatment of breast and ovarian cancers caused by mutations in the cancer susceptibility genes BRCA1 and BRCA2. These cancers are treated with a class of drugs known as PARP inhibitors that work by inhibiting a particular DNA repair factor.
The work is supported by MGH, the National Institutes of Health, the Spanish Ministry of Science and Innovation, the Carlos III Institute of Health, the Marie Curie COFUND FP7, European Research Council, and the Natural Sciences and Engineering Research Council of Canada.
Barbara Martinez-Pastor, Giorgia G. Silveira, Thomas L. Clarke, Dudley Chung, Yuchao Gu, Claudia Cosentino, Lance S. Davidow, Gadea Mata, Sylvana Hassanieh, Jayme Salsman, Alberto Ciccia, Narkhyun Bae, Mark T. Bedford, Diego Megias, Lee L. Rubin, Alejo Efeyan, Graham Dellaire, Raul Mostoslavsky. Assessing kinetics and recruitment of DNA repair factors using high content screens. Cell Reports, 2021; 37 (13): 110176 DOI: 10.1016/j.celrep.2021.110176
Scientists at Northwestern Medicine and The University of Texas MD Anderson Cancer Center have identified natural nano-bubbles containing the ACE2 protein (evACE2) in the blood of COVID-19 patients and discovered these nano-sized particles can block infection from broad strains of SARS-CoV-2 virus in preclinical studies.
The evACE2 acts as a decoy in the body and can serve as a therapeutic to be developed for prevention and treatment for current and future strains of SARS-CoV-2 and future coronaviruses, the scientists said. Once developed as a therapeutic product, it can benefit human beings as a biological treatment with minimal toxicities.
The study is the first to show evACE2 proteins are capable of fighting the new SARS-CoV-2 variants with an equal or better efficacy than blocking the original strain. The researchers found these evACE2 nano bubbles exist in human blood as a natural anti-viral response. The more severe the disease, the higher the levels of evACE2 detected in the patient's blood.
The paper will be published in Nature Communications Jan. 20.
"Whenever a new mutant strain of SARS-CoV-2 surges, the original vaccine and therapeutic antibodies may lose power against alpha, beta, delta and the most recent omicron variants," said study co-senior author Dr. Huiping Liu, an associate professor of pharmacology and of medicine at Northwestern University Feinberg School of Medicine and a Northwestern Medicine physician. "However, the beauty of evACE2 is its superpower in blocking broad strains of coronaviruses, including the current SARS-CoV-2 and even future SARS coronaviruses from infecting humans."
"Our mouse studies demonstrate the therapeutic potential of evACE2 in preventing or blocking SARS-CoV-2 infection when it is delivered to the airway via droplets," Liu said.
The evACE2 proteins are tiny lipid (fat) bubbles in nanoparticle size that express the ACE2 protein, like handles onto which the virus can grab. These bubbles act as decoys to lure the SARS-CoV-2 virus away from the ACE2 protein on cells, which is how the virus infects cells. The virus spike protein grabs the handle of evACE2 instead of cellular ACE2, preventing it from entering the cell. Once captured, the virus will either float harmlessly around or be cleared by a macrophage immune cell. At that point, it can no longer cause infection.
"The key takeaway from this study is the identification of naturally occurring extracellular vesicles in the body that express the ACE2 receptor on their surface and serve as part of the normal adaptive defense against COVID-19-causing viruses," said co-senior author Dr. Raghu Kalluri, chair of cancer biology at MD Anderson. "Building upon this, we've discovered a way to harness this natural defense as a new potential therapy against this devastating virus."
The COVID-19 pandemic has been extended and challenged by a constantly changing virus SARS-CoV-2. One of the biggest challenges is the moving target of pathogenic coronavirus that constantly evolves into new virus strains (variants) with mutations. These new viral strains harbor various changes in the viral spike protein with high infection rates and increased breakthroughs due to vaccine inefficiencies and resistance to therapeutic monoclonal antibodies.
"It remains urgent to identify novel therapeutics," Liu said. "We think evACE2 can meet the challenges and fight against broad strains of SARS-CoV-2 and future emerging coronaviruses to protect the immunocompromised (at least 2.7% of U.S. adults), unvaccinated (94% in low-income countries and more than 30% in the U.S.) and even vaccinated from breakthrough infections.
Northwestern and MD Anderson have a pending patent on evACE2. The goal is to collaborate with industry partners and develop evACE2 as a biological therapeutic product (nasal spray or injected therapeutics) for prevention and treatment of COVID-19. Liu and another co-senior author, Deyu Fang from pathology at Northwestern, have formed a startup company, Exomira, to take this patent and develop evACE2 as a therapeutic.
A team of more than 30 authors collaborated on this work. They include four lead co-first authors Lamiaa El-Shennawy, Andrew Hoffmann and Nurmaa Dashzeveg, all from the Liu lab at Northwestern, and Kathleen McAndrews from Raghu Kalluri Lab of MD Anderson. Multiple senior co-authors contributed significant work to the publication, including Northwestern colleagues Drs. Michael Ison (infectious diseases), Yuan Luo (preventive medicine), Alexis Demonbreun (pharmacology) and Daniel Batle (nephrology and hypertension), Drs. Dominique Missiakas and Glenn Randall at University of Chicago Howard T. Ricketts Laboratory and Tujin Shi at Pacific Northwest National Laboratory.
The collaboration between Northwestern and M.D. Anderson was fostered by co-author Valerie LeBleu, an MD/MBA student at Feinberg and Kellogg School of Management and formerly an assistant professor of cancer biology at MD Anderson.
The work was supported by the Chicago Biomedical Consortium Accelerator Award; Northwestern University Feinberg School of Medicine Emerging and Re-emerging Pathogens Program; the National Cancer Institute, the Blood Biobank fund; and Lyda Hill Philanthropies. Northwestern's pharmacology and pathology departments; Northwestern University Clinical and Translational Sciences Institute; and the Robert H. Lurie Comprehensive Cancer Center of Northwestern University also helped fund the work.
Story Source:
Materials provided by Northwestern University. Original written by Marla Paul. Note: Content may be edited for style and length.
Journal Reference:
Lamiaa El-Shennawy, Andrew D. Hoffmann, Nurmaa Khund Dashzeveg, Kathleen M. McAndrews, Paul J. Mehl, Daphne Cornish, Zihao Yu, Valerie L. Tokars, Vlad Nicolaescu, Anastasia Tomatsidou, Chengsheng Mao, Christopher J. Felicelli, Chia-Feng Tsai, Carolina Ostiguin, Yuzhi Jia, Lin Li, Kevin Furlong, Jan Wysocki, Xin Luo, Carolina F. Ruivo, Daniel Batlle, Thomas J. Hope, Yang Shen, Young Kwang Chae, Hui Zhang, Valerie S. LeBleu, Tujin Shi, Suchitra Swaminathan, Yuan Luo, Dominique Missiakas, Glenn C. Randall, Alexis R. Demonbreun, Michael G. Ison, Raghu Kalluri, Deyu Fang, Huiping Liu. Circulating ACE2-expressing extracellular vesicles block broad strains of SARS-CoV-2. Nature Communications, 2022; 13 (1) DOI: 10.1038/s41467-021-27893-2
The Centers for Disease Control and Prevention estimates that more than 2.8 million Americans experience antibiotic-resistant infections each year; more than 35,000 die from those infections.
To address this critical and worldwide public health issue, a team of researchers led by Hongjun (Henry) Liang, Ph.D., from the Texas Tech University Health Sciences Center (TTUHSC) Department of Cell Physiology and Molecular Biophysics, recently investigated whether or not a series of novel nanoparticles can kill some of the pathogens that lead to human infection without affecting healthy cells.
The study, "Hydrophilic Nanoparticles that Kill Bacteria while Sparing Mammalian Cells Reveal the Antibiotic Role of Nanostructures," was published Jan. 11 by Nature Communications. Other study members of the Liang team, all from TTUHSC, included Yunjiang Jiang, Ph.D., Wan Zheng, Ph.D., Keith Tran, Elizabeth Kamilar, Jitender Bariwal, Ph.D., and Hairong Ma, Ph.D.
Past research has shown that hydrophobicity (a molecule's ability to repel water) and hydrophilicity (a molecule's ability to attract and dissolve in water) affects cells; the more hydrophobic a substance is, the more adverse the reaction it will cause. However, Liang said, there is no quantitative standard for how much hydrophobicity is acceptable.
"Basically, you can kill bacteria when you increase hydrophobicity," Liang said. "But it will also kill healthy cells, and we don't want that."
For their study, the Liang team used novel hydrophilic nanoparticles known as nanoantibiotics that were developed by Liang's laboratory. Structurally speaking, these novel nanoantibiotics resemble tiny hairy spheres, each composed of many hydrophilic polymer brushes grafted onto silica nanoparticles of different sizes.
These synthetic compounds, which Liang's lab produces, are designed to kill bacteria via membrane disruptions like antimicrobial peptides do, but through a different mode of membrane remodeling that damages bacterial membranes and not mammalian cells. Antimicrobial peptides are a diverse class of amphipathic molecules (partially hydrophilic-partially hydrophobic), which occur naturally and serve as the first line of defense for all multicellular organisms. The direct use of antimicrobial peptides as antibiotics is limited by their stability and toxicity.
There have been other studies in which researchers grafted amphipathic molecules onto nanoparticles, and they too kill bacteria. However, Liang said the primary issue in using amphipathic molecules is that it becomes very difficult to strike the right balance between their hydrophobicity and hydrophilicity so that the toxicity of these molecules to our own cells is significantly reduced.
"In our case, we remove that uncertainty from the equation because we started with a hydrophilic polymer," Liang pointed out. "The cytotoxicity of hydrophobic moieties is not a concern anymore. Those hydrophilic polymers by themselves, or the silica nanoparticles alone don't kill bacteria; they have to be grafted onto the nanostructure to be able to kill bacteria. And so, this is the first important discovery."
The Liang team also discovered that the degree of antibiotic activity is affected by the size of the hairy spheres, which according to Liang is the second important discovery of this research. Those measuring 50 nanometers and below appear to be much more active than those whose size exceeds 50 nanometers. Liang said those measuring approximately 10 nanometers appear to be the most active. (Using synchrotron small angle x-ray scattering and other methods, the Liang team is able to interpret the molecular mechanism of the size-dependent antibiotic activity.)
These discoveries are important because using nanoantibiotics to kill bacteria evades all known mechanisms of bacterial resistance unless bacteria completely revamp their pathways for making cell membranes, which Liang said is unlikely.
"It is also nearly impossible for bacteria to develop new resistance against the nanoantibiotics," Liang emphasized. "Furthermore, this discovery illuminates a blueprint to develop new antibiotics that would kill bacteria upon contact, but remain amiable to humans because they are produced using non-toxic and environmentally friendly ingredients via nanoengineering."
Yunjiang Jiang, Wan Zheng, Keith Tran, Elizabeth Kamilar, Jitender Bariwal, Hairong Ma, Hongjun Liang. Hydrophilic nanoparticles that kill bacteria while sparing mammalian cells reveal the antibiotic role of nanostructures. Nature Communications, 2022; 13 (1) DOI: 10.1038/s41467-021-27193-9
Anthrax has a scary reputation. Widely known to cause serious lung infections in humans and unsightly, albeit painless, skin lesions in livestock and people, the anthrax bacterium has even been used as a weapon of terror.
Now the findings of a new study suggest the dreaded microbe also has unexpected beneficial potential -- one of its toxins can silence multiple types of pain in animals.
The research reveals that this specific anthrax toxin works to alter signaling in pain-sensing neurons and, when delivered in a targeted manner into neurons of the central and peripheral nervous system, can offer relief to animals in distress.
The work, led by investigators at Harvard Medical School in collaboration with industry scientists and researchers from other institutions, is published Dec. 20 in Nature Neuroscience.
Furthermore, the team combined parts of the anthrax toxin with different types of molecular cargo and delivered it into pain-sensing neurons. The technique can be used to design novel precision-targeted pain treatments that act on pain receptors but without the widespread systemic effects of current pain-relief drugs, such as opioids.
"This molecular platform of using a bacterial toxin to deliver substances into neurons and modulate their function represents a new way to target pain-mediating neurons," said study senior investigator Isaac Chiu, associate professor of immunology in the Blavatnik Institute at Harvard Medical School.
The need to expand the current therapeutic arsenal for pain management remains acute, the researchers said. Opioids remain the most effective pain medication, but they have dangerous side effects -- most notably their ability to rewire the brain's reward system, which makes them highly addictive, and their propensity to suppress breathing, which can be fatal.
"There's still a great clinical need for developing non-opioid pain therapies that are not addictive but that are effective in silencing pain," said study first author Nicole Yang, HMS research fellow in immunology in the Chiu Lab. "Our experiments show that one strategy, at least experimentally, could be to specifically target pain neurons using this bacterial toxin."
The researchers caution, however, that for now, this approach remains purely experimental and still needs to be tested and further fine-tuned in more animal studies and, eventually, in humans.
Primed to connect
Researchers in the Chiu lab have long been interested in the interplay between microbes and the nervous and immune systems. Past work led by Chiu has demonstrated that other disease-causing bacteria can also interact with neurons and alter their signaling to amplify pain. Yet only a handful of studies so far have looked at whether certain microbes could minimize or block pain. This is what Chiu and Yang set out to do.
For the current study, they started out by trying to determine how pain-sensing neurons may be different from other neurons in the human body. To do so, they first turned to gene-expression data. One of the things that caught their attention: Pain fibers had receptors for anthrax toxins, whereas other types of neurons did not. In other words, the pain fibers were structurally primed to interact with the anthrax bacterium. They wondered why.
The newly published research sheds light on that very question.
The findings demonstrate that pain silencing occurs when sensory neurons of dorsal root ganglia, nerves that relay pain signals to the spinal cord, connect with two specific proteins made by the anthrax bacterium itself. Experiments revealed that this occurs when one of the bacterial proteins, protective antigen (PA), binds to the nerve cell receptors it forms a pore that serves as a gateway for two others bacterial proteins, edema factor (EF) and lethal factor (LF), to be ferried into the nerve cell. The research further demonstrated PA and EF together, collectively known as edema toxin, alter the signaling inside nerve cells -- in effect silencing pain.
Using the quirks of microbial evolution for new therapies
In a series of experiments, the researchers found that the anthrax toxin altered signaling in human nerve cells in dishes, and it also did so in living animals.
Injecting the toxin into the lower spines of mice produced potent pain-blocking effects, preventing the animals from sensing high-temperature and mechanical stimulations. Importantly, the animals' other vital signs such as heart rate, body temperature, and motor coordination were not affected -- an observation that underscored that this technique was highly selective and precise in targeting pain fibers and blocking pain without widespread systemic effects.
Furthermore, injecting mice with the anthrax toxin alleviated symptoms of two other types of pain: pain caused by inflammation and pain caused by nerve cell damage, often seen in the aftermath of traumatic injury and certain viral infections such as herpes zoster, or shingles, or as a complication of diabetes and cancer treatment.
Additionally, the researchers observed that as the pain diminished, the treated nerve cells remained physiologically intact -- a finding that indicates the pain-blocking effects were not due to injury of the nerve cells but rather stemmed from the altered signaling inside them.
In a final step, the team designed a carrier vehicle from anthrax proteins and used it to deliver other pain-blocking substances into nerve cells. One of these substances was botulinum toxin, yet another potentially lethal bacterium known for its ability to alter nerve signaling. That approach, too, blocked pain in mice. The experiments demonstrate this could be a novel delivery system for targeting pain.
"We took parts of the anthrax toxin and fused them to the protein cargo that we wanted it to deliver," Yang said. "In the future, one could think of different kinds of proteins to deliver targeted treatments."
The scientists caution that as the work progresses, the safety of the toxin treatment must be monitored carefully, especially given that the anthrax protein has been implicated in disrupting the integrity of the blood-brain barrier during infection.
The new findings raise another interesting question: Evolutionarily speaking, why would a microbe silence pain?
Chiu thinks that one explanation -- a highly speculative one, he added -- may be that microbes have developed ways to interact with their host in order to facilitate their own spread and survival. In the case of anthrax, that adaptive mechanism may be through altered signaling that blocks the host's ability to sense pain and therefore the microbe's presence. This hypothesis could help explain why the black skin lesions that the anthrax bacterium sometimes forms are notably painless, Chiu added.
The new findings also point to novel avenues for drug development beyond the traditional small-molecule therapies that are currently being designed across labs.
"Bringing a bacterial therapeutic to treat pain raises the question 'Can we mine the natural world and the microbial world for analgesics?'" Chiu said. "Doing so can increase the range and diversity of the types of substances we look to in search for solutions."
Coinvestigators included Jörg Isensee, Dylan Neel, Andreza Quadros, Han-Xiong Bear Zhang, Justas Lauzadis, Sai Man Liu, Stephanie Shiers, Andreea Belu, Shilpa Palan, Sandra Marlin, Jacquie Maignel, Angela Kennedy- Curran, Victoria Tong, Mahtab Moayeri, Pascal Röderer, Anja Nitzsche, Mike Lu, Bradley Pentelute, Oliver Brüstle, Vineeta Tripathi, Keith Foster, Theodore Price, John Collier, Stephen Leppla, Michelino Puopolo, Bruce Bean, Thiago Cunha, and Tim Hucho.
This study was funded by the Burroughs Wellcome Fund; Chan-Zuckerberg Initiative; Ipsen Pharmaceuticals; National Institutes of Health (DP2AT009499, R01AI130019, R01NS036855, NIA 5T32AG000222 fellowship, NIH NIGMS T32GM007753 fellowship), and NIH NINDS (NS111929); National Institute of Allergy and Infectious Diseases Intramural Program; European Regional Development Fund (NeuRoWeg, EFRE?0800407 and EFRE?0800408); Innovative Medicines Initiative 2 Joint Undertaking (116072-NGN-PET); and São Paulo Research Foundation (2013/08216-2 Center for Research in Inflammatory Diseases); Deutsche Forschungsgemeinschaft (271522021 and 413120531), EFRE-0800384, and LeitmarktAgentur.NRW (LS-1-1-020d).
Relevant disclosures:
S.M.L., S.P., S.M., J.M., V.T., and K.A.F. are employees of Ipsen. Chiu has received sponsored research support from Ipsen, GSK, and Allergan and is a member of scientific advisory boards for GSK and Kintai Therapeutics. This work is related to patent applications PCT/US16/49099 and PCT/US16/49106, "Compositions and methods for treatment of pain," of which R.J.C., I.M.C., B.L.P., K.A.F., S.P., and S.M.L. are co- inventors. O.B. is a co-founder and shareholder of LIFE & BRAIN GmbH.
Story Source:
Materials provided by Harvard Medical School. Original written by Ekaterina Pesheva. Note: Content may be edited for style and length.
Journal Reference:
Nicole J. Yang, Jörg Isensee, Dylan V. Neel, Andreza U. Quadros, Han-Xiong Bear Zhang, Justas Lauzadis, Sai Man Liu, Stephanie Shiers, Andreea Belu, Shilpa Palan, Sandra Marlin, Jacquie Maignel, Angela Kennedy-Curran, Victoria S. Tong, Mahtab Moayeri, Pascal Röderer, Anja Nitzsche, Mike Lu, Bradley L. Pentelute, Oliver Brüstle, Vineeta Tripathi, Keith A. Foster, Theodore J. Price, R. John Collier, Stephen H. Leppla, Michelino Puopolo, Bruce P. Bean, Thiago M. Cunha, Tim Hucho, Isaac M. Chiu. Anthrax toxins regulate pain signaling and can deliver molecular cargoes into ANTXR2+ DRG sensory neurons. Nature Neuroscience, 2021; DOI: 10.1038/s41593-021-00973-8
The surging omicron variant is complicating the recovery for a world economy that continues to be wracked by supply chain chaos, worker absenteeism and faltering assembly lines.
Supermarkets are struggling to stock shelves amid chronic staff shortages. Airlines are grounding flights. Manufacturers are facing disruption and shipping lines remain backed up. At the same time, surging energy prices are adding to inflation, pressuring central banks to raise interest rates even as the recovery slows.
Optimists argue that the economic hit from omicron will be limited as vaccinations and boosters allow the disease to shift from an acute phase to an endemic one. U.S. Treasury Secretary Janet Yellen said she doesn’t expect the variant to derail the U.S. recovery.
Analysis by Nomura of omicron’s impact on nations hit early like the U.K. and Canada shows shorter duration waves, faster descents from peaks and lower death rates than the delta variant. That means the psychological fear factor could soon fade and pent-up demand for services would be unleashed.
Still, as the pandemic persists into its third year, it’s becoming clearer by the day that a return to economic normality is some way off. The global economy is now split between those countries living with the virus and China’s dogged pursuit of Covid-zero.
Such crosscurrents pose an unusual combination of challenges that risk getting baked into the longer-term outlook, according to economists at Citigroup Inc. Their counterparts at JPMorgan Chase & Co. say global growth is now downshifting because of the omicron drag.
The World Bank has already lowered its growth outlook and International Monetary Fund Managing Director Kristalina Georgieva on Friday predicted a difficult year for policy makers, saying 2022 will be like “navigating an obstacle course." The IMF will release new forecasts in coming days.
“There is a risk of underestimating the economic impact from the surge in omicron cases," said Tuuli McCully, head of Asia-Pacific economics at Scotiabank.
“While it seems that the severity of the variant is reduced and therefore the economic consequences would be milder and focused on the first quarter, it is still too early to say with certainty given that cases are skyrocketing in many parts of the world."
The infection surge comes as inflation pressures are forcing some central banks, led by the Federal Reserve, to shift toward raising interest rates. The U.S. central bank, in a meeting of the policy-setting Federal Open Market Committee this week, is expected to signal plans to raise interest rates in March for the first time since 2018.
South Korea has already raised rates this month, its third hike since the summer, and emerging economies are also tightening. China is the exception, cutting rates to shield the economy from a property slump and slowing domestic growth.
What Bloomberg’s Economists Say...
“The omicron wave sweeping the globe has already dealt a blow to the recovery. High frequency data from restaurant bookings to airline passenger numbers show demand stalling. Worker absenteeism and business closures are adding to supply stress. The good news: early evidence from the U.K. suggests the spike in omicron cases -- and impact on activity -- may end almost as quickly as it began. The big unknown: what happens if omicron collides with China’s zero-Covid strategy, pushing the world’s factory back into lockdown?"
-- Chief Economist Tom Orlik
For many economies, the disruption is real.
From Australia to the U.S. and the U.K., food supply chains for supermarkets are being disrupted and prices have soared on the back of high freight rates, poor weather, labor shortages and energy costs. Airline travel continues to be dogged by travel restrictions and staffing shortages, with thousands of flights grounded around the world.
Heavy industry is also being squeezed. Shares of Toyota Motor Corp. fell on Friday after the automaker announced expanded production halts on rising Covid-19 cases and an ongoing chip shortage impacting its suppliers and operations in Japan.
Downshifting Sales
In Europe, car sales slid for a sixth straight month in December, underscoring the uphill battle that its automakers face. Sourcing enough semiconductors will remain arduous this year, and the pandemic continues to weigh on consumer confidence.
In China, where much of the world’s industrial components and some consumer goods are produced shipping containers are stacking up at the already backed-up Shenzhen port as congestion in the U.S. and Europe ricochets back to Asia. The result: delivery delays that weigh on growth and add costs.
While China’s aggressive measures to suppress the virus has allowed factories to power through the pandemic, omicron’s spread will make that approach even more difficult. Global manufacturers operating in China, including automaker Volkswagen AG, have reported disruption due to lockdowns and other restrictions.
Among those on the front lines are global shipping companies trying to meet solid demand from consumers and businesses amid logistical constraints like port congestion, rail backups and trucker shortages. Matson Inc., a Honolulu-based container carrier, said last week that “we expect these conditions to remain largely in place through at least the October peak season and expect elevated demand for our China service for most of the year."
Hong Kong-based Willy Lin, whose company Milo’s Knitwear (International) Ltd. makes high-end sweaters from its factory in Dongguan for clients in Europe, is stocking up on key material to ensure he can meet future orders as the supply snarls continue.
“We are telling our customers, if you want to place orders you must do it now," said Lin, who is also chairman of The Hong Kong Shippers’ Council. The veteran industry player is tempering expectations for a quick return to normal.
“I am surprised that people still think these problems will go away soon," Lin said. “It’s not realistic."
In late 2020, Brianne Dressen began to spend hours in online communities for people with Long Covid, a chronic, disabling syndrome that can follow a bout with the virus. “For months, I just lurked there,” says Dressen, a former preschool teacher in Saratoga Springs, Utah, “reviewing post after post of symptoms that were just like my own.”
Dressen had never had COVID-19. But that November, she’d received a dose of AstraZeneca’s vaccine as a volunteer in a clinical trial. By that evening, her vision blurred and sound became distorted—“I felt like I had two seashells on my ears,” she says. Her symptoms rapidly worsened and multiplied, ultimately including heart rate fluctuations, severe muscle weakness, and what she describes as debilitating internal electric shocks.
A doctor diagnosed her with anxiety. Her husband, Brian Dressen, a chemist, began to comb the scientific literature, desperate to help his wife, a former rock climber who now spent most of her time in a darkened room, unable to brush her teeth or tolerate her young children’s touch.
As time passed, the Dressens found other people who had experienced serious, long-lasting health problems after a COVID-19 vaccine, regardless of the manufacturer. By January 2021, researchers at the National Institutes of Health (NIH) began to hear about such reports and sought to learn more, bringing Brianne Dressen and other affected people to the agency’s headquarters for testing and sometimes treatment.
The research was small in scale and drew no conclusions about whether or how vaccines may have caused rare, lasting health problems. The patients had “temporal associations” between vaccination and their faltering health, says Avindra Nath, clinical director at the National Institute of Neurological Disorders and Stroke (NINDS), who has been leading the NIH efforts. But “an etiological association? I don’t know.” In other words, he does not know whether vaccination directly caused the subsequent health problems.
NIH’s communications with patients faded by late 2021, though Nath says the work continues behind the scenes. The pullback caused bewilderment and dismay among patients who spoke with Science, who said the NIH researchers were the only ones helping them. Now, a small number of other researchers worldwide is beginning to study whether the biology of Long Covid, itself still poorly understood, overlaps with the mysterious mechanisms driving certain postvaccine side effects.
More discrete side effects connected to COVID-19 vaccines have been recognized, includinga rare but severe clotting disorderthat occurs after the AstraZeneca and Johnson & Johnson vaccines andheart inflammation, documented after the messenger RNA (mRNA) vaccines manufactured by Pfizer and Moderna. Probing possible side effects presents a dilemma to researchers: They risk fomenting rejection of vaccines that are generally safe, effective, and crucial to saving lives. “You have to be very careful” before tying COVID-19 vaccines to complications, Nath cautions. “You can make the wrong conclusion. … The implications are huge.” And complex and lingering symptoms like Dressen’s are even more difficult to study because patients can lack a clear diagnosis.
At the same time, understanding these problems could help those currently suffering and, if a link is nailed down, help guide the design of the next generation of vaccines and perhaps identify those at high risk for serious side effects. “We shouldn’t be averse to adverse events,” says William Murphy, an immunologist at the University of California, Davis. In November 2021 in The New England Journal of Medicine, he proposed that an autoimmune mechanism triggered by the SARS-CoV-2 spike protein might explain both Long Covid symptoms and some rare vaccine side effects, and he called for more basic research to probe possible connections. “Reassuring the public that everything is being done, researchwise, to understand the vaccines is more important than just saying everything is safe,” Murphy says. Like others, he continues to urge vaccination.
Echoes of Long Covid?
How frequently side effects like Dressen’s occur is unclear. Online communities can include many thousands of participants, but no one is publicly tracking these cases, which are variable and difficult to diagnose or even categorize. The symptoms also include fatigue, severe headaches, nerve pain, blood pressure swings, and short-term memory problems. Nath is convinced they are “extremely rare.”
Long Covid, in contrast, affects anywhere from about 5% to 30% of those infected by SARS-CoV-2. Researchers are making tentative progress with several ideas about the underlying biology. Some studies suggest the virus may in certain cases linger in tissues and cause ongoing damage. Other evidence indicates aftereffects of the original infection might play a role even after the body clears the virus.
Early clinical data point in a similar direction. Over the past year, research groups have detected unusually high levels of autoantibodies, which can attack the body’s own cells and tissues, in people after a SARS-CoV-2 infection. In Nature in May 2021, immunologists Aaron Ring and Akiko Iwasaki at Yale School of Medicine and their colleagues reported finding autoantibodies in acute COVID-19 patients that target the immune system and brain; they are now investigating how long the autoantibodies persist and whether they can damage tissues. This month, Cedars-Sinai Medical Center cardiologist Susan Cheng and protein chemist Justyna Fert-Bober wrote in the Journal of Translational Medicine that autoantibodies could last up to 6 months after infection, although the researchers did not correlate autoantibodies’ persistence with ongoing symptoms.
In part to understand whether these autoantibodies harm people, DZNE is checking the cerebrospinal fluid of Long Covid patients for antibodies that react to mouse brain tissue—if they do react, they might attack human neural tissues as well. In a paper Prüss and his colleagues are about to submit, they describe finding autoantibodies that attack mouse neurons and other brain cells in at least one-third of those patients. A group at Northwestern University, meanwhile, reported in an August 2021 preprint that in people with neurological complications after COVID-19, a subset of T cells is persistently activated as would happen with an ongoing SARS-CoV-2 infection, suggesting some sort of aberrant immune response or lingering virus.
Some researchers are looking at another possible culprit for Long Covid: tiny clots in the blood. In an acute SARS-CoV-2 infection, small clots can form that can damage cells that line blood vessels. Resia Pretorius, a physiologist at Stellenbosch University in South Africa, and her colleagues published preliminary evidence in August in Cardiovascular Diabetology that microscopic clots can linger after an infection clears. They might interfere with oxygen delivery, which could explain some Long Covid symptoms such as brain fog. Pretorius is now teaming up with colleagues to develop diagnostics for this microclotting and study ways to treat it in Long Covid.
Pretorius says she and her colleagues have also seen patients—fewer than 20, she estimates—with chronic problems following vaccination. She says these include Long Covid–like symptoms such as brain fog as well as other clotting concerns such as deep vein thrombosis. The cause of the very rare but severe clotting after the AstraZeneca and Johnson & Johnson vaccines remains unknown, but Pretorius suspects all COVID-19 vaccines might also sometimes trigger subtler clotting issues. She says she has preliminary evidence that vaccination can lead to microclots, although in most cases they go unnoticed and quickly disappear—an effect she and a colleague saw in their own blood and that of eight other healthy volunteers, which they sampled after their vaccinations.
A touchy topic
Long Covid research also brought the Dressens to Nath. In January 2021, Brian Dressen sought help from Nath, who had been studying Long Covid. Nath responded quickly and asked Brianne Dressen to join an ongoing study he leads on the natural history of inflammatory diseases of the nervous system.
Dozens more patients describing postvaccine complications found their way to Nath and Farinaz Safavi, an NINDS neurologist. “I promise you we will report your issue and other cases we are reviewing now,” Safavi wrote to Danice Hertz in March 2021. Hertz, a retired gastroenterologist who lives in Southern California, had developed debilitating side effects after one dose of the Pfizer vaccine. Senior officials at the U.S. Food and Drug Administration (FDA), the Centers for Disease Control and Prevention, and Pfizer, among others, were copied on the email, which Hertz shared with Science.
Over the first half of 2021, Nath and Safavi invited Brianne Dressen and others to NIH for testing and, in some cases, short-term treatment, for example with high-dose steroids or intravenous immunoglobulin (IVIG), which can quell or modulate immune responses. The patients spent at least several days undergoing neurological, cardiac, and other tests, including lumbar punctures and skin biopsies.
The NIH researchers were “trying to help people,” says a health care worker whose symptoms began after the Pfizer vaccine, one of four people in the study who spoke to Science. Nath says 34 people were enrolled on the protocol, 14 of whom spent time at NIH; the other 20 shipped their blood samples and in some cases cerebrospinal fluid.
As time passed, however, the patients say the NIH scientists pulled back. A September visit Brianne Dressen had scheduled for additional neurologic testing was converted to a telemedicine appointment. In December, Nath asked her to stop sending patients his way. “It is best for such patients to receive care from their local physicians,” he wrote to her.
Tubes of blood drawn from Brianne Dressen, who suffered complications after a coronavirus vaccine, are part of a National Institutes of Health study.BRI DESSEN
For patients, the silence from NIH was distressing, especially as they struggled to find care elsewhere. The scientists “took the data and left us hanging,” says a person who traveled to NIH in the spring of 2021. “I have no treatment, I have no idea what’s happening to my body.” Physicians, several patients said, had nothing to offer and sometimes even declared the symptoms imagined.
Nath told Science NIH facilities are not equipped to treat large numbers of patients long-term. Says the health care worker of the effort: “It’s too much for two people at the NIH to do.”
The NIH data, which documented the patient cases, haven’t been reported yet. Two top medical journals declined to publish a case series of about 30 people, which Nath first submitted in March 2021. Nath says he understands the rejection. The data weren’t “cut and dried; it was observational studies.” This month, the scientists submitted a case series of 23 people to a third publication, and Nath says his group has submitted an amendment to a Long Covid protocol to include patients with postvaccine side effects.
Science contacted regulators and vaccinemakers about any information they’d gleaned on these side effects. A Pfizer spokesperson wrote, “We can confirm it’s something we’re monitoring.” Moderna, AstraZeneca, and Johnson & Johnson all said they take side effects seriously and share reports they receive with regulators. An FDA spokesperson said the agency “continues to maintain a strong focus on monitoring the safety of the COVID-19 vaccines,” while the European Medicines Agency notes it “is taking steps to use real-world data from clinical practice to monitor the safety and effectiveness of COVID-19 treatments and vaccines.”
Other researchers note the scientific community is uneasy about studying such effects. “Everyone is tiptoeing around it,” Pretorius says. “I’ve talked to a lot of clinicians and researchers at various universities, and they don’t want to touch it.”
Still, her group and others are pushing ahead. Prüss has detected autoantibodies in some patients with postvaccine symptoms, although not in others. Several groups are studying whether a patient’s postvaccination symptoms are due to autoantibodies to the angiotensin-converting enzyme 2 (ACE2) receptor, which the spike protein targets. Cheng and her colleagues are planning a case series that includes sophisticated imaging and diagnostic tests from a mix of Long Covid patients and those with postvaccine side effects. And Pretorius and her colleague Chantelle Venter are hoping to recruit at least 50 people to study clotting patterns before and after vaccination.
At Yale, Iwasaki is planning to collaborate with Nath and look at any potential link between Long Covid and postvaccine effects, she says. She has spoken with affected patients and her lab intends to collect samples from them, potentially of blood or saliva. Murphy says more work is needed in animal models to trace the body’s response to vaccination. “We need to look at this in controlled situations,” he says.
Prüss is hunting for autoantibodies following COVID-19 vaccination in mice. And he continues to care for patients, both postvaccine and postinfection. His clinic hopes to soon start a clinical trial of a treatment that removes most antibodies from a patient’s blood. However, even if it works well, the procedure is expensive and might not be widely available.
Patients in the middle
People with lasting health problems after vaccination welcome any attention to their plight. “You have this ugly stain on you, and you’re marginalized and abandoned,” Brianne Dressen says. At first, “I was really afraid of causing vaccine hesitancy,” she adds.
Other patients describe vaccine opponents asserting that they deserve to die because they were foolish enough to get vaccinated. Vaccine supporters tell them that by speaking out they risk harming others, who may refuse to get vaccinated and then die from COVID-19. “We’re stuck in this horrible in-between,” says the patient who traveled to NIH last spring.
Brianne Dressen, for her part, went public. She says she was frustrated when it appeared that regulators, including FDA, were not promptly investigating the apparent side effects. She took part in a June 2021 press conference about vaccine side effects held by Senator Ron Johnson (R–WI), who has been outspoken against COVID-19 vaccinations. “Talking to politicians was not our plan A … not even close,” Brianne Dressen says. “It was more like plan J.”
Jana Ruhrländer, too, feels caught. After a single dose of the Moderna vaccine, the microbiology graduate student in Kassel, Germany, developed symptoms including the sensation of internal electric shocks Brianne Dressen experienced, partial facial paralysis, muscle weakness that left her terrified she was having seizures or a stroke, intense thirst, and wild swings in her heart rate and blood pressure. Doctors dismissed her, saying their tests found nothing wrong. She played detective, realizing her symptoms overlapped with a hormonal system called the renin-angiotensin-aldosterone system that regulates blood pressure and fluid balance—and in which ACE2 plays a key role. She has recently connected with doctors who are trying to learn whether autoantibodies targeting that system might be causing her symptoms.
Despite her experience, “I still think the vaccines are great,” Ruhrländer says. And the mRNA technology “has so much potential.” But these side effects, which for her have improved somewhat but haven’t disappeared, should be acknowledged and understood, she says. “We have to speak openly about it.”
Some of the patients who spoke with Science say medications that tamp down the immune system have offered at least a measure of relief. Nath noticed the same phenomenon. He hopes results from an NIH clinical trial testing IVIG and intravenous steroids in Long Covid patients “will be applicable to the vaccine-related complications.” None of the patients with whom Science spoke has fully recovered.
Researchers exploring postvaccine side effects all emphasize that the risk of complications from SARS-CoV-2 infection far outweighs that of any vaccine side effect. “You see 10, 100, 1000 times less risk from the vaccine,” Prüss says. But understanding the cause of postvaccine symptoms—and whether early treatment can help prevent long-term problems—could be crucial for designing even safer and more effective vaccines, Murphy says, as well as potentially providing clues to the biology of Long Covid.
Cheng has heard from dozens of people who describe chronic postvaccine problems, and she finds the overlap between their symptoms and those of Long Covid compelling. Now, she wants to move deliberately and scientifically in a search for answers. “We’ve got to retain rigor,” she says. “There’s just this complete dearth of data.”
