In the News

Immune system mounts a lasting defense after recovery from COVID-19

Poor gut health connected to severe COVID-19, new review shows

Biomarkers in mother’s plasma predict a type of autism in offspring with 100% accuracy

COVID-19 Virus Causes Lasting Vascular Dysfunction in Healthy Young Adults

Controlling pain after surgery doesn’t have to mean opioids, study shows

Immune system mounts a lasting defense after recovery from COVID-19

As the number of people who have fought off SARS-CoV-2 climbs ever higher, a critical question has grown in importance: How long will their immunity to the novel coronavirus last? A new Rockefeller study offers an encouraging answer, suggesting that those who recover from COVID-19 are protected against the virus for at least six months, and likely much longer.

The findings, published in Nature, provide the strongest evidence yet that the immune system "remembers" the virus and, remarkably, continues to improve the quality of antibodies even after the infection has waned. Antibodies produced months after the infection showed increased ability to block SARS-CoV-2, as well as its mutated versions such as the South African variant.

The researchers found that these improved antibodies are produced by immune cells that have kept evolving, apparently due to a continued exposure to the remnants of the virus hidden in the gut tissue.

Based on these findings, researchers suspect that when the recovered patient next encounters the virus, the response would be both faster and more effective, preventing re-infection.

"This is really exciting news. The type of immune response we see here could potentially provide protection for quite some time, by enabling the body to mount a rapid and effective response to the virus upon re-exposure," says Michel C. Nussenzweig, the Zanvil A. Cohn and Ralph M. Steinman Professor and head of the Laboratory of Molecular Immunology, whose team has been tracking and characterizing antibody response in Covid-19 patients since the early days of the pandemic in New York.

Long-lasting memory

Antibodies, which the body creates in response to infection, linger in the blood plasma for several weeks or months, but their levels significantly drop with time. The immune system has a more efficient way of dealing with pathogens: instead of producing antibodies all the time, it creates memory B cells that recognize the pathogen, and can quickly unleash a new round of antibodies when they encounter it a second time.

But how well this memory works depends on the pathogen. To understand the case with SARS-CoV-2, Nussenzweig and his colleagues studied the antibody responses of 87 individuals at two timepoints: one month after infection, and then again six months later. As expected, they found that although antibodies were still detectable by the six-month point, their numbers had markedly decreased. Lab experiments showed that the ability of the participants' plasma samples to neutralize the virus was reduced by five-fold.

In contrast, the patients' memory B cells, specifically those that produce antibodies against SARS-CoV-2, did not decline in number, and even slightly increased in some cases. "The overall numbers of memory B cells that produced antibodies attacking the Achilles' heel of the virus, known as the receptor-binding domain, stayed the same," says Christian Gaebler, a physician and immunologist in Nussenzweig's lab. "That's good news because those are the ones that you need if you encounter the virus again."

Viral stowaways

A closer look at the memory B cells revealed something surprising: these cells had gone through numerous rounds of mutation even after the infection resolved, and as a result the antibodies they produced were much more effective than the originals. Subsequent lab experiments showed this new set of antibodies were better able to latch on tightly to the virus and could recognize even mutated versions of it.

"We were surprised to see the memory B cells had kept evolving during this time," Nussenzweig says. "That often happens in chronic infections, like HIV or herpes, where the virus lingers in the body. But we weren't expecting to see it with SARS-CoV-2, which is thought to leave the body after infection has resolved."

SARS-CoV-2 replicates in certain cells in the lungs, upper throat, and small intestine, and residual viral particles hiding within these tissues could be driving the evolution of memory cells. To look into this hypothesis, the researchers have teamed up with Saurabh Mehandru, a former Rockefeller scientist and currently a physician at Mount Sinai Hospital, who has been examining biopsies of intestinal tissue from people who had recovered from COVID-19 on average three months earlier.

In seven of the 14 individuals studied, tests showed the presence of SARS-CoV-2's genetic material and its proteins in the cells that line the intestines. The researchers don't know whether these viral left-overs are still infectious or are simply the remains of dead viruses.

The team plans to study more people to better understand what role the viral stowaways may play in both the progression of the disease and in immunity.

Story Source: Rockefeller University.

Poor gut health connected to severe COVID-19, new review shows

People infected with COVID-19 experience a wide range of symptoms and severities, the most commonly reported including high fevers and respiratory problems. However, autopsy and other studies have also revealed that the infection can affect the liver, kidney, heart, spleen -- and even the gastrointestinal tract. A sizeable fraction of patients hospitalized with breathing problems also have diarrhea, nausea and vomiting, suggesting that when the virus does get involved in the GI tract it increases the severity of the disease.

In a review published this week in mBio, microbiologist Heenam Stanley Kim, Ph.D, from Korea University's Laboratory for Human-Microbial Interactions, in Seoul, examined emerging evidence suggesting that poor gut health adversely affects COVID-19 prognosis. Based on his analysis, Kim proposed that gut dysfunction -- and its associated leaky gut -- may exacerbate the severity of infection by enabling the virus to access the surface of the digestive tract and internal organs. These organs are vulnerable to infection because they have widespread ACE2 -- a protein target of SARS-CoV-2 -- on the surface.

"There seems to be a clear connection between the altered gut microbiome and severe COVID-19," Kim said.

Studies have demonstrated that people with underlying medical conditions including high blood pressure, diabetes and obesity face a higher risk of severe COVID-19. Risk also increases with age, with older adults most vulnerable to the most serious complications and likelihood of hospitalization. But both of these factors -- advanced age and chronic conditions -- have a well-known association with an altered gut microbiota. This imbalance can affect gut barrier integrity, Kim noted, which can allow pathogens and pathobionts easier access to cells in the intestinal lining.

So far, the link between gut health and COVID-19 prognosis hasn't been empirically demonstrated, Kim noted. Some researchers have argued, he said, that unhealthy gut microbiomes may be an underlying reason for why some people have such severe infections.

What studies have been done hint at a complicated relationship. A study on symptomatic COVID-19 patients in Singapore, for example, found that about half had a detectable level of the coronavirus in fecal tests -- but only about half of those experienced GI symptoms. That study suggests that even if SARS-CoV-2 reaches the GI tract, it may not cause problems. Kim also noted that a person's gut health at the time of infection may be critical for symptom development.

Many recent studies have found reduced bacterial diversity in gut samples collected from COVID-19 patients, compared to samples from healthy people. The disease has also been linked to a depletion of beneficial bacterial species -- and the enrichment of pathogenic ones. A similar imbalance has been associated with influenza A infection, though the 2 viruses differ in how they change the overall microbial composition.

The depleted bacterial species associated with COVID-19 infection include some families that are responsible for producing butyrate, a short-chain fatty acid, which plays a pivotal role in gut health by reinforcing gut-barrier function.

Kim said he started analyzing the studies after realizing that wealthy countries with a good medical infrastructure -- including the United States and nations in Western Europe -- were among the hardest hit by the virus. The "western diet" that's common in these countries is low in fiber, and "a fiber-deficient diet is one of the main causes of altered gut microbiomes," he said, "and such gut microbiome dysbiosis leads to chronic diseases."

The pathogenesis of COVID-19 is still not fully understood. If future studies do show that gut health affects COVID-19 prognosis, Kim argued, then clinicians and researchers should exploit that connection for better strategies aimed at preventing and managing the disease. Eating more fiber, he said, may lower a person's risk of serious disease. And fecal microbiota transplantation might be a treatment worth considering for patients with the worst cases of COVID-19.

The problem with gut health goes beyond COVID-19, though, he said. Once the pandemic passes, the world will still have to reckon with chronic diseases and other problems associated with poor gut health.

"The whole world is suffering from this COVID-19 pandemic," Kim said, "but what people do not realize is that the pandemic of damaged gut microbiomes is far more serious now."

Story Source: American Society for Microbiology.

Biomarkers in mother’s plasma predict a type of autism in offspring with 100% accuracy

Using machine learning, researchers at the UC Davis MIND Institute have identified several patterns of maternal autoantibodies highly associated with the diagnosis and severity of autism. Their study, published Jan. 22 in Molecular Psychiatry, specifically focused on maternal autoantibody-related autism spectrum disorder (MAR ASD), a condition accounting for around 20% of all autism cases.

“The implications from this study are tremendous,” said Judy Van de Water, a professor of rheumatology, allergy and clinical immunology at UC Davis and the lead author of the study. “It’s the first time that machine learning has been used to identify with 100% accuracy MAR ASD-specific patterns as potential biomarkers of ASD risk.”

Autoantibodies are immune proteins that attack a person’s own tissues. Previously, Van de Water  found that a pregnant mother’s autoantibodies can react with her growing fetus’ brain and alter its development.

Machine learning identifies patterns indicating likelihood and severity of autism

The research team obtained plasma samples from mothers enrolled in the CHARGE study. They analyzed the samples from 450 mothers of children with autism and 342 mothers of typically developing children, also from CHARGE, to detect reactivity to eight different proteins that are abundant in fetal brain. They then used a machine learning algorithm to determine which autoantibody patterns were specifically associated with a diagnosis of ASD.

The researchers created and validated a test to identify ASD-specific maternal autoantibody patterns of reactivity against eight proteins highly expressed in the developing brain.

“The big deal about this particular study is that we created a new, very translatable test for future clinical use,” said Van de Water.  This simple maternal blood test uses an ELISA (Enzyme-Linked-ImmunoSorbent Assay) platform, which is very quick and accurate.   

The machine learning program crunched roughly 10,000 patterns and identified three top patterns associated with MAR ASD: CRMP1+GDA, CRMP1+CRMP2 and NSE+STIP1.

“For example, if the mother has autoantibodies to CRIMP1 and GDA (the most common pattern), her odds of having a child with autism is 31 times greater than the general population, based on this current dataset. That’s huge,” said Van de Water. “There’s very little out there that is going to give you that type of risk assessment.”

Researchers also found that reactivity to CRMP1 in any of the top patterns significantly increases the odds of a child having more severe autism.

Future implications

Van de Water notes that with these maternal biomarkers, there are possibilities for very early diagnosis of MAR autism and more effective behavioral intervention. The study opens the door for more research on potential pre-conception testing, particularly useful for high-risk women older than 35 or who have already given birth to a child with autism.

“We can envision that a woman could have a blood test for these antibodies prior to getting pregnant. If she had them, she’d know she would be at very high risk of having a child with autism. If not, she has a 43% lower chance of having a child with autism as MAR autism is ruled out,” Van de Water said.

Van de Water is currently researching the pathologic effects of maternal autoantibodies using animal models. “We will also use these animal models to develop therapeutic strategies to block the maternal autoantibodies from the fetus,” said Van de Water.

“This study is a big deal in terms of early risk assessment for autism, and we’re hoping that this technology will become something that will be clinically useful in the future.”

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First author on the study is Alexandra Ramirez-Celis, with co-authors Joseph Schauer and Miriam Nuño from UC Davis, and Nima Aghaeepour and Martin Becker from Stanford University.

COVID-19 Virus Causes Lasting Vascular Dysfunction in Healthy Young Adults

Research Alert

Article title: Vascular alterations among young adults with SARS-CoV-2

Authors: Stephen M. Ratchford, Jonathon L. Stickford, Valesha M. Province, Nina Stute, Marc A. Augenreich, Laurel K. Koontz, Landry K. Bobo, Abigail S.L. Stickford

From the authors: “Using a cross-sectional design, this study assessed vascular function [three to four weeks] after young adults tested positive for SARS-CoV-2. The main findings from this study were a strikingly lower vascular function and a higher arterial stiffness compared with healthy controls. Together, these results suggest rampant vascular effects seen weeks after contracting SARS-CoV-2 in young adults.”

See original study     link  https://doi.org/10.1152/ajpheart.00897.2020

Controlling pain after surgery doesn’t have to mean opioids, study shows

 As surgeons balance the need to control their patients’ post-surgery pain with the risk that a routine operation could become the gateway to long-term opioid use or addiction, a new study shows the power of an approach that takes a middle way.

In a new letter in JAMA Surgery, a team from Michigan Medicine at the University of Michigan reports on findings from a study of 620 patients who had surgery in hospitals across Michigan, had their painkiller use tracked, and took surveys within one to three months after their operations.

Half of the patients received pre-surgery counseling that emphasized non-opioid pain treatment as their first option. Some patients in this group received small, “just in case” prescriptions, but a third of them didn’t receive any opioid prescription at all after surgery.

The other patients received standard care – meaning they got the usual amount of opioids given after these operations. Not only did every patient in that group get an opioid prescription, those prescriptions tended to be larger than those in the other group. And most patients didn’t take them all – leaving extra pills that can pose a hazard to the patient or others in their household if taken inappropriately, or diverted to illicit use.

The patients in the two groups had the same operations – gallbladder removal, full or partial thyroid removal or hernia repair. But despite the difference in painkiller use, the patients in both groups were equally satisfied with their care and reported similar quality of life when contacted later. And those in the opioid-sparing group actually reported experiencing less pain overall.

First author Maia Anderson, M.D., a resident in the U-M Department of Surgery, says, “It’s so exciting to think about the potential for opioid sparing postoperative pathways to not only reduce the risk of opioids for our patients, but also to substantially decrease the risk of opioid diversion into our communities.”

Senior author and surgical resident Ryan Howard, M.D., adds, “We know that opioids pose serious risks to patients after surgery. We can protect patients from those risks by reducing or eliminating opioids after surgery. But that idea always raises the concern that patients will have uncontrolled pain and feel miserable. This study suggests that’s not the case – patients who get small opioid prescriptions, or even no prescription, are just as satisfied with their recovery after surgery.”

Anderson and Howard worked with the three U-M Medical School faculty who direct the Michigan Opioid Prescribing and Engagement Network, and with Alex Hallways, B.S., a member of the program’s staff who coordinates the effort to right-size surgery-related opioid prescribing in Michigan. Michigan-OPEN has published evidence-based prescribing guidelines for many procedures, as well as materials to support opioid-sparing patient education.

The study used data from the Michigan Surgical Quality Consortium that is working to improve surgical care in 70 hospitals across Michigan. Anderson and Howard are fellows of the U-M Center for Healthcare Outcomes and Policy.