Virus World

Coronavirus Disease 2019 (COVID-19) vaccines protect the public and limit viral spread. However, inactivated viral vaccines use the whole virus particle, which contains many non-capsid proteins that may cause adverse immune responses. A report has found that the ADP-ribose-binding domains of SARS-CoV-2 non-structural protein 3 (NSP3) and human poly(ADP-ribose) polymerase family member 14 (PARP14) share a significant degree of homology. Here, we further show that antibodies against 2019 novel SARS-like coronavirus (SARS-CoV-2) NSP3 can bind human PARP14 protein. However, when G159R + G162R mutations were introduced into NSP3, the antibody titer against human PARP14 decreased 14-fold.

Antibodies against SARS-CoV-2 NSP3 can cross-react with human skeletal muscle cells and astrocytes, but not human embryonic kidney 293T cells. However, when G159R + G162R mutations were introduced into NSP3, the cross-reaction was largely inhibited. The results imply that COVID-19 patients with high antibody titers against NSP3 may have high risks of muscular and/or neurological complications. And the possible strategies to improve the safety of inactivated viral vaccines are also discussed.

Published in Vaccine (Jan. 27, 2024): https://doi.org/10.1016/j.vaccine.2024.01.074

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

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

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

New findings by scientists at the National Institutes of Health and their collaborators help explain why some people with COVID-19 develop severe disease. The findings also may provide the first molecular explanation for why more men than women die from COVID-19. The researchers found that more than 10% of people who develop severe COVID-19 have misguided antibodies―autoantibodies―that attack the immune system rather than the virus that causes the disease. Another 3.5% or more of people who develop severe COVID-19 carry a specific kind of genetic mutation that impacts immunity. Consequently, both groups lack effective immune responses that depend on type I interferon, a set of 17 proteins crucial for protecting cells and the body from viruses. Whether these proteins have been neutralized by autoantibodies or―because of a faulty gene―were produced in insufficient amounts or induced an inadequate antiviral response, their absence appears to be a commonality among a subgroup of people who suffer from life-threatening COVID-19 pneumonia.

These findings are the first published results from the COVID Human Genetic Effort(link is external), an international project spanning more than 50 genetic sequencing hubs and hundreds of hospitals. The effort is co-led by Helen Su, M.D., Ph.D., a senior investigator at the National Institute of Allergy and Infectious Diseases (NIAID), part of NIH; and Jean-Laurent Casanova, M.D., Ph.D., head of the St. Giles Laboratory of Human Genetics of Infectious Diseases at The Rockefeller University in New York. Major contributions were made by Luigi Notarangelo, M.D., chief of the NIAID Laboratory of Clinical Immunology and Microbiology (LCIM); Steven Holland, M.D., director of the NIAID Division of Intramural Research and senior investigator in the NIAID LCIM; clinicians and investigators in hospitals in the Italian cities of Brescia, Monza and Pavia, which were heavily hit by COVID-19; and researchers at the Uniformed Services University of the Health Sciences in Bethesda, Maryland. The wide variation in the severity of disease caused by SARS-CoV-2, the virus behind COVID-19, has puzzled scientists and clinicians. SARS-CoV-2 can cause anything from a symptom-free infection to death, with many different outcomes in between. Since February 2020, Drs. Su and Casanova and their collaborators have enrolled thousands of COVID-19 patients to find out whether a genetic factor drives these disparate clinical outcomes.

The researchers discovered that among nearly 660 people with severe COVID-19, a significant number carried rare genetic variants in 13 genes known to be critical in the body’s defense against influenza virus, and more than 3.5% were completely missing a functioning gene. Further experiments showed that immune cells from those 3.5% did not produce any detectable type I interferons in response to SARS-CoV-2. Examining nearly 1,000 patients with life-threatening COVID-19 pneumonia, the researchers also found that more than 10% had autoantibodies against interferons at the onset of their infection, and 95% of those patients were men. Biochemical experiments confirmed that the autoantibodies block the activity of interferon type I.

Original Studies Published  in Science  (Sept.  24, 2020):

https://doi.org/10.1126/science.abd4570

https://doi.org/10.1126/science.abd4585

Patients infected with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) can experience life-threatening respiratory distress, blood pressure dysregulation and thrombosis. This is thought to be associated with an impaired activity of angiotensin-converting enzyme-2 (ACE-2), which is the main entry receptor of SARS-CoV-2 and which also tightly regulates blood pressure by converting the vasoconstrictive peptide angiotensin II (AngII) to a vasopressor peptide. Here, we show that a significant proportion of hospitalized COVID-19 patients developed autoantibodies against AngII, whose presence correlates with lower blood oxygenation, blood pressure dysregulation, and overall higher disease severity. Anti-AngII antibodies can develop upon specific immune reaction to the SARS-CoV-2 proteins Spike or RBD, to which they can cross-bind, suggesting some epitope mimicry between AngII and Spike/RBD. These results provide important insights on how an immune reaction against SARS-CoV-2 can impair blood pressure regulation.

Available as Preprint at medRxiv (Nov. 2, 2021):

 https://doi.org/10.1101/2021.11.02.21265789 

Evidence is growing that self-attacking ‘autoantibodies’ could be the key to understanding some of the worst cases of SARS-CoV-2 infection.   More than a year after COVID-19 emerged, many mysteries persist about the disease: why do some people get so much sicker than others? Why does lung damage sometimes continue to worsen well after the body seems to have cleared the SARS-CoV-2 virus? And what is behind the extended, multi-organ illness that lasts for months in people with ‘long COVID’? A growing number of studies suggest that some of these questions might be explained by the immune system mistakenly turning against the body — a phenomenon known as autoimmunity. “This is a rapidly evolving area, but all the evidence is converging,” says Aaron Ring, an immunologist at the Yale School of Medicine in New Haven, Connecticut.

Early in the pandemic, researchers suggested that some people have an overactive immune response to COVID infection. Immune-system signalling proteins called cytokines can ramp up to dangerous levels, leading to ‘cytokine storms’ and damage to the body’s own cells. Clinical trials have now shown that some drugs that broadly dampen immune activity seem to reduce death rates in critically ill people, if administered at the right time. But scientists studying COVID are increasingly also highlighting the role of autoantibodies: rogue antibodies that attack either elements of the body’s immune defences or specific proteins in organs such as the heart. In contrast to cytokine storms, which tend to cause systemic, short-duration problems, autoantibodies are thought to result in targeted, longer-term damage, says immunologist Akiko Iwasaki, a colleague of Ring’s at Yale.  Even healthy people make autoantibodies, but not generally in large amounts, and the molecules don’t usually seem to cause damage or attack the immune system. Yet researchers also have evidence that nefarious autoantibodies do have a role in many infectious diseases. There are several theories to explain how autoimmunity might emerge from COVID and other infections. Some people might be predisposed to producing autoantibodies that can then wreak havoc during an infection. Alternatively, infections could even trigger the production of autoantibodies. If researchers can establish the link, they might be able to come up with avenues for treatment, both for the repercussions of COVID and for other diseases caused by viruses.

Finding autoantibodies

In late September, a group led by Jean-Laurent Casanova at the Rockefeller University in New York City reported that more than 10% of 987 individuals with severe COVID-19 had antibodies that attacked and blocked the action of type 1 interferon molecules, which normally help to bolster the immune response against foreign pathogens1. That was a striking proportion, the researchers say, because people’s antibody repertoires are normally very dissimilar, and no one in a control group for the study had these antibodies. The researchers also saw the antibodies in people before their COVID-19 infection, so Casanova thinks that some people could be genetically predisposed to produce them. And the autoantibodies were more common in men than women — a possible factor in why COVID seems to hit men harder. The first evidence suggesting that autoantibodies against interferon might put people at higher risk of infectious disease was published in 1984, and evidence has accumulated since then, Casanova says. But now COVID is drawing more attention to the connection. “Now people understand the problem,” he says, “and all of a sudden they realize that what my lab has been doing for 25 years is actually pretty meaningful.” Casanova is now screening 40,000 people to see how many have pre-existing autoantibodies and determine whether their distribution by age, ancestry and gender matches that of severe COVID. Other research groups have supported Casanova’s autoantibody connection. Iwasaki, Ring and others screened 194 patients and hospital workers with varying severities of COVID for a wide range of autoantibodies. Their study, which was posted online in December and has not yet been peer reviewed, found a higher prevalence of autoantibodies against the immune system in infected individuals than in uninfected people. They found autoantibodies that attacked B cells, as well as some that attacked interferon.....

Published in Nature (Jan. 19, 2021):

https://doi.org/10.1038/d41586-021-00149-1