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Autoantibodies against type I IFNs in patients with life-threatening COVID-19

Science

The immune system is complex and involves many genes, including those that encode cytokines known as interferons (IFNs). Individuals that lack specific IFNs can be more susceptible to infectious diseases. Furthermore, the autoantibody system dampens IFN response to prevent damage from pathogen-induced inflammation. Two studies now examine the likelihood that genetics affects the risk of severe coronavirus disease 2019 (COVID-19) through components of this system (see the Perspective by Beck and Aksentijevich). Q. Zhang et al. used a candidate gene approach and identified patients with severe COVID-19 who have mutations in genes involved in the regulation of type I and III IFN immunity. They found enrichment of these genes in patients and conclude that genetics may determine the clinical course of the infection. Bastard et al. identified individuals with high titers of neutralizing autoantibodies against type I IFN-α2 and IFN-ω in about 10% of patients with severe COVID-19 pneumonia. These autoantibodies were not found either in infected people who were asymptomatic or had milder phenotype or in healthy individuals. Together, these studies identify a means by which individuals at highest risk of life-threatening COVID-19 can be identified. Science , this issue p. [eabd4570][1], p. [eabd4585][2]; see also p. [404][3] ### INTRODUCTION Interindividual clinical variability is vast in humans infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), ranging from silent infection to rapid death. Three risk factors for life-threatening coronavirus disease 2019 (COVID-19) pneumonia have been identified—being male, being elderly, or having other medical conditions—but these risk factors cannot explain why critical disease remains relatively rare in any given epidemiological group. Given the rising toll of the COVID-19 pandemic in terms of morbidity and mortality, understanding the causes and mechanisms of life-threatening COVID-19 is crucial. ### RATIONALE B cell autoimmune infectious phenocopies of three inborn errors of cytokine immunity exist, in which neutralizing autoantibodies (auto-Abs) against interferon-γ (IFN-γ) (mycobacterial disease), interleukin-6 (IL-6) (staphylococcal disease), and IL-17A and IL-17F (mucocutaneous candidiasis) mimic the clinical phenotypes of germline mutations of the genes that encode the corresponding cytokines or receptors. Human inborn errors of type I IFNs underlie severe viral respiratory diseases. Neutralizing auto-Abs against type I IFNs, which have been found in patients with a few underlying noninfectious conditions, have not been unequivocally shown to underlie severe viral infections. While searching for inborn errors of type I IFN immunity in patients with life-threatening COVID-19 pneumonia, we also tested the hypothesis that neutralizing auto-Abs against type I IFNs may underlie critical COVID-19. We searched for auto-Abs against type I IFNs in 987 patients hospitalized for life-threatening COVID-19 pneumonia, 663 asymptomatic or mildly affected individuals infected with SARS-CoV-2, and 1227 healthy controls from whom samples were collected before the COVID-19 pandemic. ### RESULTS At least 101 of 987 patients (10.2%) with life-threatening COVID-19 pneumonia had neutralizing immunoglobulin G (IgG) auto-Abs against IFN-ω (13 patients), against the 13 types of IFN-α (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three individual type I IFNs. These auto-Abs neutralize high concentrations of the corresponding type I IFNs, including their ability to block SARS-CoV-2 infection in vitro. Moreover, all of the patients tested had low or undetectable serum IFN-α levels during acute disease. These auto-Abs were present before infection in the patients tested and were absent from 663 individuals with asymptomatic or mild SARS-CoV-2 infection ( P < 10−16). They were present in only 4 of 1227 (0.33%) healthy individuals ( P < 10−16) before the pandemic. The patients with auto-Abs were 25 to 87 years old (half were over 65) and of various ancestries. Notably, 95 of the 101 patients with auto-Abs were men (94%). ### CONCLUSION A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men. In these patients, adaptive autoimmunity impairs innate and intrinsic antiviral immunity. These findings provide a first explanation for the excess of men among patients with life-threatening COVID-19 and the increase in risk with age. They also provide a means of identifying individuals at risk of developing life-threatening COVID-19 and ensuring their enrolment in vaccine trials. Finally, they pave the way for prevention and treatment, including plasmapheresis, plasmablast depletion, and recombinant type I IFNs not targeted by the auto-Abs (e.g., IFN-β). ![Figure][4] Neutralizing auto-Abs to type I IFNs underlie life-threatening COVID-19 pneumonia. We tested the hypothesis that neutralizing auto-Abs against type I IFNs may underlie critical COVID-19 by impairing the binding of type I IFNs to their receptor and the activation of the downstream responsive pathway. Neutralizing auto-Abs are represented in red, and type I IFNs are represented in blue. In these patients, adaptive autoimmunity impairs innate and intrinsic antiviral immunity. ISGs, IFN-stimulated genes; TLR, Toll-like receptor; IFNAR, IFN-α/β receptor; pSTAT, phosphorylated signal transducers and activators of transcription; IRF, interferon regulatory factor. Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-ω (IFN-ω) (13 patients), against the 13 types of IFN-α (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men. [1]: /lookup/doi/10.1126/science.abd4570 [2]: /lookup/doi/10.1126/science.abd4585 [3]: /lookup/doi/10.1126/science.abe7591 [4]: pending:yes


Researchers find evidence of racial, gender, and socioeconomic bias in chest X-ray classifiers

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Google and startups like Qure.ai, Aidoc, and DarwinAI are developing AI and machine learning systems that classify chest X-rays to help identify conditions like fractures, collapsed lungs, and fractures. Several hospitals including Mount Sinai have piloted computer vision algorithms that analyze scans from patients with the novel coronavirus. But research from the University of Toronto, the Vector Institute, and MIT reveals that chest X-ray datasets used to train diagnostic models exhibit imbalance, biasing them against certain gender, socioeconomic, and racial groups. Partly due to a reticence to release code, datasets, and techniques, much of the data used today to train AI algorithms for diagnosing diseases may perpetuate inequalities. A team of U.K. scientists found that almost all eye disease datasets come from patients in North America, Europe, and China, meaning eye disease-diagnosing algorithms are less certain to work well for racial groups from underrepresented countries.


How a Montreal chatbot provider is using CRM to drive revenue

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Heyday co-founders Steve Desjarlais, left, and Étienne Mérineau stand in the company's Montreal office on Sept. 30, 2020. When COVID-19 hit, forcing people to stay home, Heyday AI knew its chatbot technology would be vital for retailers that could no longer converse with their customers in person. But the Montreal-based company also knew landing new clients would be a challenge given the cancellation of big tech events where it often drums up business face-to-face. "A lot of [those] sales ... bank on relationships, and therefore you need to meet in person," says Étienne Mérineau, who co-founded Heyday in 2017 with Steve Desjarlais, David Bordeleau and Hugues Rousseau. Heyday uses artificial intelligence to help retailers communicate with customers on websites and across various apps and programs such as Facebook Messenger and Google Maps.


How AI is helping combat homelessness in Canada during COVID-19

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"It is paramount to think about not just what our data is used for, but (also) 'what can our data be used for in the future?' - and assume whoever holds the data has no scruples," said Paulo Garcia, assistant professor of computer engineering at Ottawa's Carleton University.


Reimagining the new social contract for the digital age

ZDNet

This TechRepublic Premium ebook compiles the latest on cancelled conferences, cybersecurity attacks, remote work tips, and the impact this pandemic is having on the tech industry. Don Tapscott is one of the world's leading authorities on the impact of technology on business and society having authored 16 widely read books. He has coined many concepts that are part of the business lexicon today and is sought by corporate and government leaders globally. Tapscott is currently co-founder and executive chairman of the Blockchain Research Institute, an adjunct professor at INSEAD, recently a two-term chancellor of Trent University in Ontario, and a Member of The Order of Canada. Tapscott is ranked the second-most influential Management Thinker and the top Digital Thinker in the world by Thinkers50.


Toronto will test Olli driverless shuttles to boost its transit system

Engadget

Self-driving shuttles in North America aren't limited to the US. The city of Toronto has struck a deal with Local Motors to use the latest version of its Olli driverless shuttles as part of an automated transportation trial in spring 2021. The six- to 12-month test run will gauge how well the autonomous vehicles will bolster Toronto's mass transit system by connecting the West Rouge neighborhood with its local Go train station. The Olli 2.0 shuttles have space for up to eight passengers. Commuters won't be completely alone, though -- two staffers (one from Pacific Western Transportation and one from either TTC or Metrolinx) will be onboard to study each trip.


Exporters Embrace Automation to Stimulate Productivity and Profits

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Coronavirus pandemic has made many things evident to Canadian exporters, including the fact that investing in automation and technology is the future of exporting. President and chief executive officer of Canadian Manufacturers and Exporters (CME), Dennis Darby says, firms that invested in automation are now availing benefits wherein those that didn't are trying to catch up. "The first group is now saying that we need more new technology to meet demand while the other is saying that it's a time to re-think operations." He adds, "With physical distancing and worker absenteeism two key challenges amid COVID-19 pandemic, many Canadian exporters find themselves in the latter category." There's no surprise given the historical lack of investment in automation.


News at a glance

Science

SCI COMMUN### Politics The U.S. presidential race was upended in the first days of October as President Donald Trump tested positive for the pandemic virus and spent 3 days in the hospital. He was aggressively treated with two experimental medicines—monoclonal antibodies and the repurposed antiviral remdesivir—and a steroid used in severe COVID-19 cases. Trump returned to the White House on 5 October saying people should not fear the disease. But public health specialists voiced astonishment when he re-entered the building maskless, trailed by questions about his medical condition and a lack of information about how staff members would be protected from infection. All that followed a rancorous first debate on 29 September between Trump and Democratic challenger Joe Biden. Trump mocked Biden for having worn a mask at other times, despite evidence that the precaution reduces transmission of the virus. The president also left scientists puzzled when he described as a “disaster” Biden's role in the response to the H1N1 swine flu outbreak in 2009. Then-President Barack Obama, whom Biden served under as vice president, declared it a public health emergency 6 weeks before the World Health Organization declared a pandemic. That flu killed an estimated 12,000 Americans—far fewer than the 210,000 U.S. deaths recorded so far from COVID-19. > “Very few don't have some sort of connection to Big Tech.” > > Doctoral student Mohamed Abdalla , in Wired , about a study he led of faculty members specializing in artificial intelligence at four leading research universities. He found 58% (48 of 83) had received a grant or fellowship from one of 14 large technology companies, which may distort research priorities. ### Conservation High-tech fake turtle eggs can spy on poachers and wildlife trafficking routes. The real eggs are a delicacy in Central America, and illicit trading of them adds to other hazards to the survival of turtle species that are threatened. Researchers slipped 101 decoy eggs with GPS trackers embedded (left) into nests on four Costa Rican beaches. The scientists tracked five eggs to learn where the poachers took them; the farthest ended up 137 kilometers inland, the multinational team reported on 5 October in Current Biology . The researchers did not share this information with authorities, noting ethical concerns; many poachers live in poverty, and in Costa Rica, buying the eggs is not illegal. But, the authors say, the study shows that law enforcement agencies could use the method. ### Public health Coronavirus guidelines issued last week by the U.S. Centers for Disease Control and Prevention (CDC) again stirred controversy and concerns that undue political pressure had influenced some of its decisions. CDC announced that on 31 October it will lift an order barring cruise ships from sailing despite a recommendation by its director, Robert Redfield, to extend the ban until February 2021. The industry shut down in March after severe COVID-19 outbreaks occurred on multiple ships. Last week, CDC also drew fire for its updated guidelines on when colleges should test students and faculty and staff members for the pandemic virus. The agency recommended different frequencies of testing, including just a single, initial one, depending on circumstances such as whether students lived in residences with others who tested positive. Critics said the new guidelines should have recommended more regular testing of asymptomatic individuals. CDC addressed another uproar this week by acknowledging evidence that the virus can travel by air and infect people standing more than 2 meters apart in indoor spaces. The agency was faulted last month after it posted, and then withdrew, a draft suggesting otherwise. ### Infectious diseases An international program to reduce the risk of new zoonotic diseases, allowed to expire by the U.S. government in 2019 but extended until last month, will get a successor. On 30 September, the United States Agency for International Development (USAID) awarded a $100 million grant to help countries in Asia and Africa curb viruses jumping from animals to humans. The 5-year Strategies to Prevent Spillover program will have a different focus from its predecessor, PREDICT, whose termination was criticized by the scientific community: Rather than studying the drivers of spillover, it will seek interventions to reduce viral jumps, a USAID spokesperson says. A key goal is to “help partners at the country level build their expertise and ability to take action,” says veterinarian Deborah Kochevar of Tufts University, which leads a 13-institute consortium that won the grant. ### International affairs Yuri Orlov, the Russian physicist who championed human rights in the Soviet Union before being exiled in 1985, died on 27 September at age 96. Orlov helped organize the Soviet Union's branch of Amnesty International in 1973 and 3 years later co-founded the Moscow Helsinki Group, which monitored Soviet adherence to the civil rights provisions of the 1975 Helsinki Accords between the Soviet Union and the West. In 1977, Orlov was arrested and sentenced to 12 years of hard labor and exile in Siberia. After coming to the United States in a prisoner exchange, Orlov, an expert in particle accelerators, worked at Cornell University. He didn't think much of Russian President Vladimir Putin, writing in 2004 that “Russia is flying backward in time.” ### Governance Japan's new prime minister, Yoshihide Suga, has disrupted the process by which scientists are appointed to serve on the governing body of the country's leading academic society, the Science Council of Japan (SCJ). Researchers are criticizing the move as a threat to academic freedom. SCJ makes policy recommendations, promotes scientific literacy and international cooperation, and represents the interests of more than 800,000 scholars in virtually all academic disciplines. The prime minister customarily ratifies appointees recommended by SCJ for its governing body, the General Assembly. But according to an announcement last week, Suga withheld his blessing from six academics, in a list of 105 put forward, who work in the social sciences, law, and the humanities. All six had criticized legislation adopted by Japan's previous government, in which Suga was chief cabinet secretary. His failure to appoint them violated a law governing SCJ, said Satoshi Ihara, secretary general of the Japan Scientists' Association. ### Policy Mexican scientists this week blasted a move by the national legislature to eliminate 109 trust funds run by public research centers and government institutes, one-third of them devoted to science and technology. The government wants to use the money, some $3 billion in total, for the coronavirus pandemic. The funds support everything from student scholarships and emergency maintenance of equipment to major research projects at dozens of government centers. The money also helps pay for biosecurity and biotechnology research, fighting climate change, and disaster relief. On 6 October, Mexico's Chamber of Deputies approved a bill to terminate the funds, but with “reservations” that require further debate; it is expected to pass in the Senate. The plan is “a brutal blow” and the worst hit to Mexican science in 50 years, says Antonio Lazcano, an evolutionary biologist at the National Autonomous University of Mexico, University City. ### Virology There's been a new case of infection with Alaskapox virus, a recently discovered pathogen that's related to smallpox. Alaska state health authorities reported on 30 September that they had found the virus in a woman from the Fairbanks area with a mild, gray skin lesion on one arm, similar to one seen in 2015 in the first known patient, also a woman from Fairbanks. Human infections with pox-viruses are on the rise, presumably because vaccination against smallpox—which offers some protection against related viruses—was halted after that deadly disease was eradicated 40 years ago. But the Alaska cases are no cause for alarm: There is no evidence the virus can be transmitted between humans—scientists think it came from wild mammals—and the lesions went away by themselves. ### Medicine prize goes to discoverers of virus that destroys the liver The Nobel Prize in Physiology or Medicine was awarded this week for the discovery of the hepatitis C virus, one of the most common causes of liver cancer. The prize went to Harvey Alter of the U.S. National Institutes of Health; Michael Houghton of the University of Alberta, Edmonton; and Charles Rice of Rockefeller University. The hepatitis C virus, transmitted via blood, can cause chronic inflammation of the liver that quietly destroys the organ over decades, ultimately leading to cirrhosis and cancer. The laureates did work over 3 decades to identify the virus and show it was responsible for unexplained cases of hepatitis in people who received blood transfusions. They also developed a test to screen blood donations for the virus, which has nearly eliminated the risk of hepatitis from blood transfusions. Their research ultimately led to a successful treatment for the disease, which has cured millions of people. But about 71 million people worldwide still have chronic hepatitis C, and transmission continues via contaminated medical equipment, sharing drug injection needles, and from infected mothers to newborns during birth. The disease causes few acute symptoms, and testing in many developing countries is limited. ### Black hole hunters receive physics prize The Nobel Prize in Physics has been awarded for pioneering discoveries regarding black holes—self-sustaining gravitational fields so intense that nothing, not even light, can escape. Roger Penrose, a mathematician at the University of Oxford, received half of the $1.1 million prize for his theoretical work, conducted in part with the late Stephen Hawking, that proved a black hole would be stable and thus could be a real astrophysical object and not a mere mathematical curiosity. Astronomers Reinhard Genzel of the Max Planck Institute for Extraterrestrial Physics and Andrea Ghez of the University of California, Los Angeles, share the other half of the prize for deducing the presence of the supermassive black hole that lies in the heart of our Galaxy. Since the 1990s, Genzel and Ghez have led rival research groups that observed stars there, 26,000 light-years from Earth. They found ones orbiting a heavy, unseen object, called Sagittarius A*, at incredible speeds—some of the most convincing evidence for a behemoth black hole, with the mass of millions of Suns. ### Fauci: ‘Skunk at the picnic’ On 23 September, in the relative calm before President Donald Trump's coronavirus infection was revealed, Anthony Fauci relaxed at home after tangling earlier that day with U.S. Senator Rand Paul (R–KY) during a hearing on COVID-19. Fauci still had 200 emails in his inbox to read that night, but the head of the National Institute of Allergy and Infectious Diseases, who also serves on the White House's Coronavirus Task Force, sat down with Science to discuss the pandemic and research on vaccines. (Read the full interview at [scim.ag/FauciOctober][1].) Some excerpts: On his showdown with Paul: “I said to myself, you know, ‘I'm sorry, I'm not gonna disrespect him, but I'm not gonna let him get away with saying things that are cherry-picked data.’” (Paul had suggested that the United States follow Sweden's COVID-19 policies because it had a lower death rate from the disease.) On speaking bluntly at the White House: “I'm walking a fine line of being someone who is not hesitant to tell the president and the vice president what they may not want to hear. There are some people in the White House, who, even when I first started telling it like it was in the task force meetings, they were like, ‘Oh my goodness.’ That's when I got that nickname ‘the skunk at the picnic.’ … I say, ‘I'm sorry, I'm not trying to undermine the president. But there is something that's called reality.’” On the state of the pandemic: “Yes, there are parts of the country that are doing well. But this country is a big forest, and when you have fires in some parts of the forest, the entire forest is at risk.” [1]: http://scim.ag/FauciOctober


UMD Center for Machine Learning Announces 2020 Class of Rising Stars

#artificialintelligence

The University of Maryland Center for Machine Learning will host four female researchers this fall as part of a program that encourages and supports underrepresented doctoral candidates whose scientific work is focused on machine learning. Diana Cai, Irene Chen, Mahsa Ghasemi and Nan Rosemary Ke (pictured clockwise from top left) were recently selected as this year's Rising Stars in Machine Learning based on their novel research, academic accomplishments and exceptional work experience. The Rising Stars program, launched by the center last year, is focused on supporting upper-level graduate students from disadvantaged or underrepresented groups as they pursue new scientific discoveries and academic opportunities in machine learning. This year's cohort--who hail from Princeton University, the Massachusetts Institute of Technology, the University of Texas at Austin and the University of Montreal--were chosen from a competitive pool of 17 applicants. "After extensive review, we chose these four candidates based on their record of excellence in research and scholarship," said Soheil Feizi, assistant professor of computer science and a core faculty member in the Center for Machine Learning.


The Rise Of Restaurant Robots Amidst Pandemic Measures

#artificialintelligence

In a restaurant landscape where lean profit margins are getting even slimmer due to the necessary COVID-19 safety measures of distancing, staying afloat is an increasingly difficult challenge. Small wonder, then, that some operators are using whatever means they can to stand out from their competition. Robot waiters, although not a new phenomenon, are making headlines around the world again, but this time with a socially distanced twist. At Claypot Rice, a Chinese restaurant in Calgary, robot greeters and servers chat with guests, take orders and run food from the kitchen. These are typically three distinct roles performed by humans, a fact not lost on owner Alex Guo.