Virus World

Highlights

Summary

Researchers found associations between certain viral illnesses and the risk of Alzheimer’s and other neurodegenerative diseases.  Neurodegenerative diseases can damage different parts of the nervous system, including the brain. This may lead to problems with thinking, memory, and/or movement. Examples include Alzheimer’s disease (AD), multiple sclerosis (MS), and Parkinson’s disease (PD). These diseases tend to happen late in life. There are few effective treatments. Previous findings have suggested that viruses may play a role in certain neurodegenerative diseases. For example, a recent study found a link between Epstein-Barr virus infection and the risk of MS. There are also concerns about cognitive impacts from SARS-CoV-2, the virus that causes COVID-19. A research team led by Drs. Mike Nalls, Kristin Levine, and Hampton Leonard of NIH's Center for Alzheimer’s and Related Dementias examined links between viruses and neurodegenerative disease more generally. To do so, they analyzed data from the FinnGen project. This is a repository of biomedical data, or biobank, from more than 300,000 people in Finland. The team searched the biobank for people who had been diagnosed with one of six different conditions: AD, amyotrophic lateral sclerosis (ALS), generalized dementia, vascular dementia, PD, and MS. They then checked how many had been hospitalized for a viral illness before. To confirm their findings, they looked for the same associations in the UK Biobank, which contains data from almost 500,000 people in the United Kingdom. Results appeared in Neuron on January 19, 2023.

The researchers found 45 associations between viruses and neurodegenerative diseases in FinnGen. Of these, 22 also appeared in the UK Biobank. The strongest association was between viral encephalitis—brain inflammation caused by a virus—and AD. A person with viral encephalitis in the FinnGen database was 30 times as likely to be diagnosed with AD as someone without encephalitis. Results were similar in the UK Biobank; people with viral encephalitis were 22 times as likely to develop AD as those without. The team also found, in FinnGen, the association between Epstein-Barr virus and MS that was described before. The association wasn’t seen in the UK Biobank, but this may reflect how the different biobanks use hospital diagnostic codes; Epstein-Barr viruses are common and so often not noted. Influenza with pneumonia was associated with all the neurodegenerative diseases except MS. The researchers only included cases of influenza severe enough to need hospitalization in the study. Thus, these associations only apply to the most severe cases of influenza. FinnGen contains data on the same people over time. The team used this to examine how the associations depended on the time since infection. They found that some viral infections were associated with increased risk of neurodegenerative disease as much as 15 years later. The researchers note that vaccines exist for some of the viruses they identified. These include influenza, varicella-zoster (which causes chickenpox and shingles), and certain pneumonia-causing viruses. Vaccination might thus reduce some of the risk of the conditions they examined. “The results of this study provide researchers with several new critical pieces of the neurodegenerative disorder puzzle,” Nalls says. “In the future, we plan to use the latest data science tools to not only find more pieces but also help researchers understand how those pieces, including genes and other risk factors, fit together.”

Some people develop multiple sclerosis after an infection. Could a vaccine prevent that — and what does it reveal about the long-term effects of viruses?  In a sprawling facility in Silver Spring, Maryland, the US Department of Defense (DoD) has amassed a hoard of epidemiological treasure. Walk-in freezers each the size of a basketball court hold 72 million vials of blood serum meticulously tracked and sorted into cardboard boxes stacked nearly 4 metres high. Technicians pull on winter coats and gloves for 20-minute trips into these −30 °C deep freezers. The vials they bring out hold untold riches. For Alberto Ascherio, an epidemiologist at Harvard T.H. Chan Medical School in Boston, Massachusetts, the vials have yielded a rare gift in the quest to discover the cause of multiple sclerosis (MS), a disease in which the immune system attacks nerve cells. Researchers have long suspected a link between MS and the Epstein–Barr virus (EBV), but it has been hard to establish a strong connection, partly because almost everyone gets an EBV infection at some point, most of them harmless. The samples in the DoD’s freezers provided an unparalleled chance to explore the link. After analysing data and samples collected from more than 10 million army, navy and air force service members since 1993, Ascherio found that EBV infection increases the risk of MS 32-fold1. 

“I’ve never seen anything so strong, so black and white,” says Ascherio. Smoking increases the risk of lung cancer 15–30-fold. These results, combined with emerging mechanistic insight into how the virus triggers brain damage2, are raising the prospect of treating and even preventing MS. A phase I trial of an EBV vaccine is under way, although it will be years, if not decades, before large trials can shed light on whether vaccines forestall MS.  These advances come at a time when researchers are more interested than ever in what happens months and years after a viral infection. Two years into the coronavirus pandemic, huge numbers of people face lasting symptoms after their initial infection with SARS-CoV-2. Concern over long COVID looms large for both the public and health officials, and funders have poured more than US$1 billion dollars into understanding the biology of this nebulous post-viral condition. The longer-running effort to understand the causes of MS highlights the problems and promise of untangling the complex relationships between infectious diseases and later chronic conditions. Progress with these investigations can seem slow, but Katherine Luzuriaga, a clinician-scientist specializing in childhood infectious diseases at UMass Chan Medical School in Worcester, Massachusetts, has faith in the steady march of science. “As scientific methods and technologies evolve,” she says, “I think we’re going to get a lot more insights into post-viral conditions.....”

Background:

Infections can trigger exacerbations of multiple sclerosis (MS). The effects of the coronavirus disease 2019 (COVID-19) on MS are not known. The aim of this study was to understand the impact of COVID-19 on new and pre-existing symptoms of MS.

Methods:

The COVID-19 and MS study is an ongoing community-based, prospective cohort study conducted as part of the United Kingdom MS Register. People with MS and COVID-19 were invited by email to complete a questionnaire about their MS symptoms during the infection. An MS exacerbation was defined as developing new MS symptoms and/or worsening of pre-existing MS symptoms.

Results:

Fifty-seven percent (230/404) of participants had an MS exacerbation during their infection; 82 developed new MS symptoms, 207 experienced worsened pre-existing MS symptoms, and 59 reported both. Disease modifying therapies (DMTs) reduced the likelihood of developing new MS symptoms during the infection (OR 0.556, 95%CI 0.316-0.978). Participants with a higher pre-COVID-19 webEDSS (web-based Expanded Disability Status Scale) score (OR 1.251, 95%CI 1.060-1.478) and longer MS duration (OR 1.042, 95%CI 1.009-1.076) were more likely to experience worsening of their pre-existing MS symptoms during the infection.

Conclusion:

COVID-19 infection was associated with exacerbation of MS. DMTs reduced the chance of developing new MS symptoms during the infection.

Preprint available at medRxiv (March 10, 2021):

https://doi.org/10.1101/2021.03.08.21253141 

Gut microbes produce compounds that prime immune cells to destroy harmful viruses in the brain and nervous system. The findings suggest that having healthy and diverse microbiota is essential for quickly clearing viruses in the nervous system to prevent paralysis and other risks associated with diseases such as multiple sclerosis. 

"We wanted to investigate whether gut microbes could alter the immune response to a virus in the central nervous system and whether this affects the amount of damage the virus causes," says one of the lead authors David Garrett Brown, a graduate research assistant in the Department of Pathology at University of Utah Health, Salt Lake City, US.

To do this, Garrett Brown and co-lead author Ray Soto looked at the effect of Mouse Hepatitis Virus, a virus that infects cells in the mouse nervous system and causes multiple-sclerosis type symptoms, on two groups of mice: some with normal gut microbes and some that were bacteria-free. They found that bacteria-free mice had a weak immune response, were unable to eliminate the virus and developed worsening paralysis, while those with normal gut bacteria were better able to fight off the virus. Mice treated with antibiotics before the onset of disease were unable to defend themselves. They also had fewer immune cells called microglia, which help flag viruses for destruction by other immune cells.

The studies were published today in eLife:

 https://doi.org/10.7554/eLife.47117

UChicago Pritzker Molecular Engineering research could yield treatments with fewer side effects. A new type of vaccine developed by researchers at the University of Chicago’s Pritzker School of Molecular Engineering has shown that it can reverse autoimmune diseases like multiple sclerosis and type 1 diabetes in lab tests — all without shutting down the rest of the immune system. Trials are only just beginning in humans, but researchers say the method holds promise. “In the past, we showed that we could use this approach to prevent autoimmunity,” said Jeffrey Hubbell, the Eugene Bell Professor in Tissue Engineering and lead author of the new paper. “But what is so exciting about this work is that we have shown that we can treat diseases like multiple sclerosis after there is already ongoing inflammation, which is more useful in a real-world context.” A typical vaccine teaches the human immune system to recognize a virus or bacteria as an enemy that should be attacked. The new “inverse vaccine” does just the opposite: it removes the immune system’s memory of one molecule. While such immune memory erasure would be unwanted for infectious diseases, it can stop autoimmune reactions like those seen in multiple sclerosis, type I diabetes, or rheumatoid arthritis, in which the immune system attacks a person’s healthy tissues.

Unwinding an immune response

The job of the immune system’s T cells is to recognize unwanted cells and molecules — from viruses and bacteria to cancers — as foreign to the body and get rid of them. Once T cells launch an initial attack against an antigen, they retain a memory of the invader to eliminate it more quickly in the future. T cells can make mistakes, however, and recognize healthy cells as foreign. In people with multiple sclerosis, for instance, T cells mount an attack against myelin, the protective coating around nerves. Today, autoimmune diseases are generally treated with drugs that broadly shut down the immune system. “These treatments can be very effective, but you’re also blocking the immune responses necessary to fight off infections and so there are a lot of side effects,” said Hubbell. Hubbell and his colleagues wanted to explore an alternative approach. They knew that the body has a mechanism for ensuring that immune reactions don’t occur in response to every damaged cell in the body — a phenomenon known as peripheral immune tolerance, which is carried out in the liver. They discovered in recent years that tagging molecules with a sugar known as N-acetylgalactosamine (pGal) could mimic this process, sending the molecules to the liver where tolerance to them develops.

“The idea is that we can attach any molecule we want to pGal and it will teach the immune system to tolerate it,” explained Hubbell. “Rather than rev up immunity as with a vaccine, we can tamp it down in a very specific way with an inverse vaccine.” In the new study, the researchers focused on a multiple-sclerosis-like disease in which the immune system attacks myelin, leading to weakness and numbness, loss of vision and, eventually mobility problems and paralysis. The team linked myelin proteins to pGal and tested the effect of the new inverse vaccine in animals. The immune system, they found, stopped attacking myelin, allowing nerves to function correctly again and reversing symptoms of disease. In a series of other experiments, the scientists showed that the same approach worked to minimize other ongoing immune reactions.

Toward clinical trials

Initial phase I safety trials of a glycosylation-modified antigen therapy based on this preclinical work have already been carried out in people with celiac disease, and phase I safety trials are under way in multiple sclerosis. Those trials are conducted by the pharmaceutical company Anokion SA, which helped fund the new work and which Hubbell cofounded and is a consultant, board member, and equity holder. The Alper Family Foundation also helped fund the research. “There are no clinically approved inverse vaccines yet, but we’re incredibly excited about moving this technology forward,” said Hubbell.

Research cited published (Sept. 7, 2023) in Nat. Biomedical Engineering:

 https://doi.org/10.1038/s41551-023-01086-2 

The jab could ward off Epstein-Barr virus, which causes glandular fever and is increasingly being linked to multiple sclerosis, lymphoma and stomach cancer.  A vaccine that wards off the common Epstein-Barr virus to potentially prevent glandular fever, multiple sclerosis (MS) and even some cancers has shown promise in mice, ferrets and monkeys. A human trial is expected to start in 2023. Gary Nabel at ModeX Therapeutics in Natick, Massachusetts, and his colleagues developed a vaccine that exposes the body to two proteins that Epstein-Barr virus uses to invade cells, training the immune system to recognise the pathogen if exposed. Initial experiments have shown that mice, ferrets and rhesus macaques developed antibodies against Epstein-Barr virus post-vaccination. To better understand the jab’s potential in people, the researchers engineered mice with human-like immune systems. When exposed to Epstein-Barr virus, only 17 per cent of the mice became infected after receiving antibodies from other vaccinated rodents. In contrast, 100 per cent of the mice without antibodies became infected. “It was a very promising result because we were able to basically block the virus infection almost entirely and stop it from causing even low-level infection,” says Nabel.

None of the mice that received the vaccine-induced antibodies developed lymphomas, cancers of the lymphatic system that are increasingly being linked to Epstein-Barr virus, compared with half of the unprotected rodents. The researchers didn’t look into any other Epstein-Barr-related conditions, such as stomach cancer. More than 95 per cent of adults worldwide are infected with Epstein-Barr virus, a type of herpes that most commonly spreads via saliva. It is known to cause glandular fever, also called “mono”, and is associated with MS. If the vaccine is shown to be safe and effective in people, it could be given to children to prevent Epstein-Barr-related conditions, says Nabel. Moderna, the US company better known for its covid-19 vaccine, recently began a clinical trial for its own Epstein-Barr jab. Moderna’s vaccine differs from the ModeX candidate in that, similarly to its covid-19 jab, it uses mRNA to instruct cells to make several Epstein-Barr virus proteins, rather than administering them directly. Julia Morahan at MS Australia says both vaccines look promising, but MS is a progressive disease and it will be several decades before we can gauge their potential. “If we were able to give every child a vaccine, we would then have to wait a solid 25 years to see if they develop MS,” she says.

Original research published in Science Translational Medicine  (May 4, 2022):

10.1126/scitranslmed.abf3685 

Infectious mononucleosis in childhood, especially in adolescence, appeared to increase risk for an MS diagnosis, independent of shared familial factors, according to results of a population-based cohort study published in JAMA Network Open. “Infectious mononucleosis has previously been associated with MS, but it has been suggested that this is because people with genetic susceptibility to MS have an immune system that is more reactive to Epstein-Barr virus infection (the virus that causes infectious mononucleosis),” Scott Montgomery, PhD, director of clinical epidemiology and biostatistics at Örebro University Hospital in Sweden, told Healio Neurology. “This would mean that more severe infectious mononucleosis, possibly resulting in hospital admission, would be observed more often in people who would go on to develop MS anyway, irrespective of whether they had infectious mononucleosis or not.  “It has also been argued that family circumstances in childhood might influence both infectious mononucleosis risk and MS risk, such that the infection is an epiphenomenon rather than a cause of MS,” Montgomery added.

In the current study, Montgomery and colleagues sought to determine whether hospital-diagnosed infectious mononucleosis in childhood, adolescence or young adulthood was linked to subsequent MS diagnosis unrelated to shared familial factors. According to Montgomery, if infectious mononucleosis is indeed a risk factor for MS, comparing siblings would show this connection, and associations that arise entirely from shared familial characteristics would not appear. The researchers analyzed data of 2,492,980 individuals (52.63% men) included in the Swedish Total Population Register who were born in Sweden between 1958 and 1994. Follow-up occurred among participants beginning at age 20 years in 1978 and continued until 2018, with a median follow-up of 15.38 years. Infectious mononucleosis diagnosis before age 25 years served as the exposure. MS diagnoses from age 20 years served as the main outcome. Montgomery and colleagues used conventional and stratified Cox proportional hazards regression to address familial environmental or genetic confounding and, in turn, estimate the risk for an MS diagnosis linked to infectious mononucleosis from childhood, adolescence and early adulthood.

Results showed an MS diagnosis among 5,867 (0.24%) participants from age 20 years (median age, 31.5 years). Infectious mononucleosis in childhood (HR = 1.98; 95% CI, 1.21-3.23) and adolescence (HR = 3; 95% CI, 2.48-3.63) correlated with an increased risk for an MS diagnosis. This risk remained significant after controlling for shared familial factors in stratified Cox proportional hazards regression. Infectious mononucleosis in early adulthood also correlated with risk for a subsequent MS diagnosis (HR = 1.89; 95% CI, 1.18-3.05); however, controlling for shared familial factors attenuated this risk and made it nonsignificant (HR = 1.51; 95% CI, 0.82-2.76). “MS should be considered as a potential diagnosis at an earlier time in patients with neurological symptoms and signs and a history of infectious mononucleosis in adolescence,” Montgomery said. “Although only a small proportion of those who have severe infectious mononucleosis in adolescence will go on to develop MS, limiting acute CNS involvement may have long-term benefits for this minority.”

Researchers link the Human Herpes Virus 6A to the development of multiple sclerosis. Researchers at Karolinska Institutet have developed a new method to separate between two different types of a common herpes virus (HHV-6) that has been linked to multiple sclerosis. By analyzing antibodies in the blood against the most divergent proteins of herpesvirus 6A and 6B, the researchers were able to show that MS-patients carry the herpesvirus 6A to a greater extent than healthy individuals. The findings, published in Frontiers in Immunology, point to a role for HHV-6A in the development of MS. 

Multiple sclerosis, MS, is an autoimmune disease that affects the central nervous system. The cause of the disease is unclear, but one plausible explanation is a virus tricks the immune system to attack the body's own tissue. Human Herpesvirus 6 (HHV-6) has previously been associated with MS, but in those studies it wasn't possible to distinguish between 6A and 6B. Through virus isolation from ill individuals, researchers have been able to show that HHV-6B can cause mild conditions such as roseola in children, but it has been unclear if HHV-6A is the cause of any disease. According to estimates, as many as 80 percent of all children are infected with the HHV-6 virus before 2 years of age, and many also carry protection in the form of antibodies against this particular virus for the rest of their lives. But since it hasn't been possible to tell the two variants apart post-infection, it has been difficult to say whether HHV-6A or B is a risk factor for MS. In this study, however, the researchers were able to distinguish between the A and B virus by analyzing antibodies in the blood against the proteins--immediate early protein 1A and 1B (IE1A and IE1B)--that diverge the most between the two viruses.

The researchers compared antibody levels in blood samples of some 8,700 MS-patients against more than 7,200 healthy people whose gender, date of birth, date of blood sample and other factors matched those with MS. They concluded that people with MS had a 55 percent higher risk of carrying antibodies against the HHV-6A protein than the control group. In a sub-group of almost 500 people, whose blood samples were drawn before the onset of the disease, the risk of developing MS in the future was more than doubled if they had a 6A viral infection. The younger the people were when the virus was first discovered in the blood, the higher the risk was of developing MS in the future. HHV-6B, on the other hand, was not positively associated with MS. Instead MS-patients had lower levels of antibodies toward IE1B than those without MS. 

Antibodies toward Epstein-Barr virus (EBV), another herpes virus that is also associated with MS, were analyzed with the same method and the researchers were able to show that individuals affected with both viruses had an even greater risk of MS. This indicates that several virus infections could be acting jointly to increase the risk of MS. "Both HHV-6A and 6B can infect our braincells, but they do it in slightly different ways. Therefore, it is now interesting to go forward and attempt to map out exactly how the viruses could affect the onset of MS," says Anna Fogdell-Hahn.

Published in Frontiers  in Immunology (26 November 2019):

https://doi.org/10.3389/fimmu.2019.02715