Publisher Health

Shigella bacteria can infect humans but not mice. In the March 29 issue of Nature, a team from UConn Health explains why. Their findings may explain the multifariousness of a key weapon of our immune system.
Shigella infections cause fever, stomach pain, and prolonged, sometimes bloody diarrhea for as long as a week. The bacteria sicken 450,000 people each year in the US alone. Although most people recover on their own, children and those with weakened immune systems are at risk of Shigella infections spreading to their bloodstream and causing kidney damage. Shigella infections are a significant cause of sickness and disability, but it’s difficult to study the bacteria because it only sickens primates like humans and apes — not animals easy to study in a lab. The bacteria cannot infect more typical lab animals such as mice.
Previous research had looked at how Shigella interacts with gasdermin-B, a critical part of our immune system that helps protect us against infection. Gasdermin-B is member of a protein family called gasdermin, which includes gasdermin-A, -B, -C, -D, -E and -F. It was thought that when gasdermin-B detects an invader, such as bacteria, it begins to poke holes in the cell’s wall, causing it to burst open and release chemicals that induce inflammation and call reinforcements from the immune system. But the past research studies on gasdermin-B were contradictory; some confirmed its role in cell death during infection, but others contradicted the idea.
UConn School of Medicine immunologist Jianbin Ruan and a team of colleagues from UConn Health wanted to clarify whether gasdermin-B actually does cause cell death in the case of microbial invasion; they also wanted to figure out why it doesn’t do this when Shigella is the invader.
The team needed to take a close look at gasdermin-B. They expressed the protein, purified it, and then cooled the protein down to very low temperatures so it would hold still while they took pictures of it with an electron microscope.
“We collected hundreds of thousands of images to build the 3D models of protein molecules at the atomic level. Through these models we will understand what these proteins look like and how they do their job,” said Chengliang Wang, research fellow in the Ruan lab and first author of the study.
Their research confirms previous research and provides evidence that Shigella bacteria grab onto a specific segment of gasdermin-B in humans. However, the mouse version of the protein has a different shape that prevents Shigella from latching onto it, resulting in the rapid clearance of the bacteria and preventing infection. This finding helps explain why Shigella is unable to infect mice.
Since human gasdermin-B can be configured in six slightly differing proteins, or isoforms, the team expressed all six then looked at how these isoforms behaved inside cells, and they found something surprising: some of the isoforms of gasdermin-B did indeed poke holes to cause cell death — but other isoforms did not.
“Previously, people didn’t understand why studies contradicted each other. We show that only two of the isoforms of gasdermin-B cause pyroptosis, or cell death,” says Ruan. Those two isoforms contain a specific protein segment that is absent in the other gasdermin-B isoforms, as shown by their cryogenic electron microscopy structure.
The finding may explain many mysteries of cell death, and life. Cancer cells, for example, are notoriously long lived and unlikely to die via pyroptosis. It may be that these cancer cells express only gasdermin-B isoforms that don’t poke holes in cell walls.
However, we don’t yet know what these other isoforms are doing. It may be that the different isoforms of gasdermin-B play significant and distinctive roles depending on where they are in the body, and different cell types preferentially express different isoforms.
“The protein structures that our team discovered have significant implications for drug development. Specifically, they can inform the design of small molecule drugs that modulate gasdermin-B activity,” explains Ruan. “These drugs could potentially be used to treat a range of conditions, including cancer, inflammatory and autoimmune diseases, and infectious diseases by either suppressing or enhancing the immune response. Our findings thus hold promise for the development of novel therapies to address these pressing medical needs.”

When patients request or demand an antibiotic, even when it is unlikely to help, a physician might be tempted to give in and write a prescription, especially if they’re working in a busy setting like an urgent care or emergency department.
However, a major new study by researchers at Intermountain Health and Stanford University finds that overprescribing and inappropriate prescribing of antibiotics is not only leading to antibiotic resistance — but also causing significant patient harm. It’s one of the most comprehensive studies to document the impact of antibiotic overuse in clinical practice.
Every year, there are enough outpatient antibiotics prescribed in the US to cover 80% of the population. The new study, published in the Journal of Internal Medicine, examined 51 million patient encounters over a 15-year-period and focused on upper respiratory infections where antibiotics were known to be overprescribed 50% of the time.
Researchers found that some of the most dangerous antibiotics were rarely indicated and commonly used, leading to one in 300 of those patients experiencing side effects dire enough to require a follow up doctor’s visit — or even hospitalization.
This study was one of the few studies large enough to estimate serious, but rare, adverse events such as a potentially deadly diarrheal infection, Clostridium difficile. With previous studies showing 34 Million unnecessary antibiotic prescriptions annually in the US, this translates to real harm for many patients and families.
“These findings underscore that inappropriately giving patients antibiotics is causing real and widespread harm,” said Harris Carmichael, MD, principal investigator of the study and hospitalist at Intermountain Health in Salt Lake City. “Having these kinds of side effects for one in a few hundred, or even a thousand, patients may not seem like a lot, but when you look at this problem on a population health level, we’re talking about hundreds of thousands of adverse events severe enough that these patients needed additional care from a doctor.”
That means time off work and school for families, unnecessary doctor visits, and risks of serious infections that can last for months or years.

In the retrospective study, researchers from Intermountain and Stanford reviewed insurance claims from the Clinformatics Data Mark Database.
Using data from Medicare Advantage and commercial insurance patients in all 50 states, inpatient and outpatient administrative claims, pharmaceutical claims, and patient demographics for beneficiaries seen between December 2002 and December 2017, they found 50.9 million claims for upper respiratory infections, including sinusitis, pharyngitis, laryngitis, bronchitis and the common cold, representing 23 million unique patients.
Researchers then identified instances when patients did and did not receive oral antibiotics for an upper respiratory infection, and if those patients were diagnosed with either diarrhea, candidiasis, Clostridium difficile infection or a mix of these side effects thereafter.
They found that 62.4% of these upper respiratory infection patients filled a prescription for an antibiotic, consistent with prior studies of this population. Following their initial visits, 26% of those patients had a follow-up outpatient visit within 14 days.
The odds of a patient being diagnosed with an adverse event increased 30% for those receiving antibiotics. Adverse events following antibiotics were found in as many as one in 300 prescriptions, depending on the antibiotic prescribed, or one in 1,150 prescriptions overall.

“With millions of visits for upper respiratory infections in the United States each year, the extent of these severe adverse events is significant,” said Dr. Carmichael.
Researchers also found that the antibiotic Cefdinir was the fourth most prescribed antibiotic for these patients, despite it rarely being recommended by prescription guidelines as an appropriate treatment for simple upper respiratory infections.
This drug also had the second highest chance of leading to an adverse event. That means that patients are being prescribed a medication that is either not needed at all or unlikely to be the most appropriate medication for their condition and is routinely causing harm, said Dr. Carmichael.
He added that the chance of adverse events is likely much higher, as these results only capture follow-up visits where their adverse event was coded as such for insurance purposes.
That means the results do not include adverse events where physicians didn’t code for that specific side effect, nor for patients who weren’t sick enough to be seen in a doctor’s office but may still have had additional and unnecessary time for recovery.
These findings point to the increasingly important need for antibiotic stewardship programs, so that physicians are following prescribing guidelines and “only prescribe antibiotics when necessary, and then it’s the right antibiotics for the right condition,” said Dr. Carmichael.
When Intermountain implemented their own enhanced antibiotic stewardship programs, which included explaining to patients why they weren’t being prescribed an antibiotic if they asked for it, the health system reduced their overall prescribing rates by more than 15%.
“Patients don’t get upset when they don’t get antibiotics, as long as we take the time to explain their condition and that we’re treating them in the way that is best for them,” said Dr. Carmichael.

Researchers at Boston University, USA report that the flow of cerebrospinal fluid in the brain is linked to waking brain activity. Led by Stephanie Williams, and publishing in the open access journal PLOS Biology on March 30th, the study demonstrates that manipulating blood flow in the brain with visual stimulation induces complementary fluid flow. The findings could impact treatment for conditions like Alzheimer’s disease, which have been associated with declines in cerebrospinal fluid flow.
Just as our kidneys help remove toxic waste from our bodies, cerebrospinal fluid helps remove toxins from the brain, particularly while we sleep. Reduced flow of cerebrospinal fluid is known to be related to declines in brain health, such as occur in Alzheimer’s disease. Based on evidence from sleep studies, the researchers hypothesized that brain activity while awake could also affect the flow of cerebrospinal fluid. They tested this hypothesis by simultaneously recording human brain activity via fMRI and the speed of cerebrospinal fluid flow while people were shown a checkered pattern that turned on and off.
Researchers first confirmed that the checkered pattern induced brain activity; blood oxygenation recorded by fMRI increased when the pattern was visible and decreased when it was turned off. Next, they found that the flow of cerebrospinal fluid negatively mirrored the blood signal, increasing when the checkered pattern was off. Further tests showed that changing how long the pattern was visible affected blood and fluid in a predictable way, and that the blood-cerebrospinal fluid link could not be accounted for by only breathing or heart rate rhythms.
Although the study did not measure waste clearance from the brain, it establishes that simple exposure to a flashing pattern can increase the flow of cerebrospinal fluid, which could be a way to combat natural or unnatural declines in fluid flow that occur with age or disease.
Laura Lewis, senior author of the study, adds, “This study discovered that we can induce large changes in cerebrospinal fluid flow in the awake human brain, by showing images with specific patterns. This result identifies a noninvasive way to modulate fluid flow in humans.”

A common amino acid, glycine, can deliver a “slow-down” signal to the brain, likely contributing to major depression, anxiety and other mood disorders in some people, scientists at the Wertheim UF Scripps Institute for Biomedical Innovation & Technology have found.
The discovery, outlined Thursday in the journal Science, improves understanding of the biological causes of major depression and could accelerate efforts to develop new, faster-acting medications for such hard-to-treat mood disorders, said neuroscientist Kirill Martemyanov, Ph.D., corresponding author of the study.
“Most medications for people with depression take weeks before they kick in, if they do at all. New and better options are really needed,” said Martemyanov, who chairs the neuroscience department at the institute in Jupiter.
Major depression is among the world’s most urgent health needs. Its numbers have surged in recent years, especially among young adults. As depression’s disability, suicide numbers and medical expenses have climbed, a study by the U.S. Centers for Disease Control and Prevention in 2021 put its economic burden at $326 billion annually in the United States.
Martemyanov said he and his team of students and postdoctoral researchers have spent many years working toward this discovery. They didn’t set out to find a cause, much less a possible treatment route for depression. Instead, they asked a basic question: How do sensors on brain cells receive and transmit signals into the cells? Therein lay the key to understanding vision, pain, memory, behavior and possibly much more, Martemyanov suspected.
“It’s amazing how basic science goes. Fifteen years ago we discovered a binding partner for proteins we were interested in, which led us to this new receptor,” Martemyanov said. “We’ve been unspooling this for all this time.”
In 2018 the Martemyanov team found the new receptor was involved in stress-induced depression. If mice lacked the gene for the receptor, called GPR158, they proved surprisingly resilient to chronic stress.

That offered strong evidence that GPR158 could be therapeutic target, he said. But what sent the signal?
A breakthrough came in 2021, when his team solved the structure of GPR158. What they saw surprised them. The GPR158 receptor looked like a microscopic clamp with a compartment — akin to something they had seen in bacteria, not human cells.
“We were barking up the completely wrong tree before we saw the structure,” Martemyanov said. “We said, ‘Wow, that’s an amino acid receptor. There are only 20, so we screened them right away and only one fit perfectly. That was it. It was glycine.”
That wasn’t the only odd thing. The signaling molecule was not an activator in the cells, but an inhibitor. The business end of GPR158 connected to a partnering molecule that hit the brakes rather than the accelerator when bound to glycine.
“Usually receptors like GPR158, known as G protein Coupled Receptors, bind G proteins. This receptor was binding an RGS protein, which is a protein that has the opposite effect of activation,” said Thibaut Laboute, Ph.D., a postdoctoral researcher from Martemyanov’s group and first author of the study.

Scientists have been cataloging the role of cell receptors and their signaling partners for decades. Those that still don’t have known signalers, such as GPR158, have been dubbed “orphan receptors.”
The finding means that GPR158 is no longer an orphan receptor, Laboute said. Instead, the team renamed it mGlyR, short for “metabotropic glycine receptor.”
“An orphan receptor is a challenge. You want to figure out how it works,” Laboute said. “What makes me really excited about this discovery is that it may be important for people’s lives. That’s what gets me up in the morning.”
Laboute and Martemyanov are listed as inventors on a patent application describing methods to study GPR158 activity. Martemyanov is a cofounder of Blueshield Therapeutics, a startup company pursuing GPR158 as a drug target.
Glycine itself is sold as a nutritional supplement billed as improving mood. It is a basic building block of proteins and affects many different cell types, sometimes in complex ways. In some cells, it sends slow-down signals, while in other cell types, it sends excitatory signals. Some studies have linked glycine to the growth of invasive prostate cancer.
More research is needed to understand how the body maintains the right balance of mGlyR receptors and how brain cell activity is affected, he said. He intends to keep at it.
“We are in desperate need of new depression treatments,” Martemyanov said. “If we can target this with something specific, it makes sense that it could help. We are working on it now.”
The research was supported by the National Institute of Health’s National Institute of Mental Health (MH105482) and National Institute of General Medical Sciences (GM069832).

A new artificial intelligence tool can predict the functions of enzymes based on their amino acid sequences, even when the enzymes are unstudied or poorly understood. The researchers said the AI tool, dubbed CLEAN, outperforms the leading state-of-the-art tools in accuracy, reliability and sensitivity. Better understanding of enzymes and their functions would be a boon for research in genomics, chemistry, industrial materials, medicine, pharmaceuticals and more.
“Just like ChatGPT uses data from written language to create predictive text, we are leveraging the language of proteins to predict their activity,” said study leader Huimin Zhao, a University of Illinois Urbana-Champaign professor of chemical and biomolecular engineering. “Almost every researcher, when working with a new protein sequence, wants to know right away what the protein does. In addition, when making chemicals for any application — biology, medicine, industry — this tool will help researchers quickly identify the proper enzymes needed for the synthesis of chemicals and materials.”
The researchers will publish their findings in the journal Science and make CLEAN accessible online March 31.
With advances in genomics, many enzymes have been identified and sequenced, but scientists have little or no information about what those enzymes do, said Zhao, a member of the Carl R. Woese Institute for Genomic Biology at Illinois.
Other computational tools try to predict enzyme functions. Typically, they attempt to assign an enzyme commission number — an ID code that indicates what kind of reaction an enzyme catalyzes — by comparing a queried sequence with a catalog of known enzymes and finding similar sequences. However, these tools don’t work as well with less-studied or uncharacterized enzymes, or with enzymes that perform multiple jobs, Zhao said.
“We are not the first one to use AI tools to predict enzyme commission numbers, but we are the first one to use this new deep-learning algorithm called contrastive learning to predict enzyme function. We find that this algorithm works much better than the AI tools that are used by others,” Zhao said. “We cannot guarantee everyone’s product will be correctly predicted, but we can get higher accuracy than the other two or other three methods.”
The researchers verified their tool experimentally with both computational and in vitro experiments. They found that not only could the tool predict the function of previously uncharacterized enzymes, it also corrected enzymes mislabeled by the leading software and correctly identified enzymes with two or more functions.

Zhao’s group is making CLEAN accessible online for other researchers seeking to characterize an enzyme or determine whether an enzyme could catalyze a desired reaction.
“We hope that this tool will be used widely by the broad research community,” Zhao said. “With the web interface, researchers can just enter the sequence in a search box, like a search engine, and see the results.”
Zhao said the group plans to expand the AI behind CLEAN to characterize other proteins, such as binding proteins. The team also hopes to further develop the machine-learning algorithms so that a user could search for a desired reaction and the AI would point to a proper enzyme for the job.
“There are a lot of uncharacterized binding proteins, such as receptors and transcription factors. We also want to predict their functions as well,” Zhao said. “We want to predict the functions of all proteins so that we can know all the proteins a cell has and better study or engineer the whole cell for biotechnology or biomedical applications.”
The National Science Foundation supported this work through the Molecule Maker Lab Institute, an AI Research Institute Zhao leads.
Further information: https://moleculemaker.org/alphasynthesis/

Aging, or senescent cells, which stop dividing but don’t die, can accumulate in the body over the years and fuel chronic inflammation that contributes to conditions such as cancer and degenerative disorders.
In mice, eliminating senescent cells from aging tissues can restore tissue balance and lead to an increased healthy lifespan. Now a team led by investigators at Massachusetts General Hospital (MGH), a founding member of Mass General Brigham (MGB), has found that the immune response to a virus that is ubiquitously present in human tissues can detect and eliminate senescent cells in the skin.
For the study, which is published in Cell, the scientists analyzed young and old human skin samples to learn more about the clearance of senescent cells in human tissue.
The researchers found more senescent cells in the old skin compared with young skin samples. However, in the samples from old individuals, the number of senescent cells did not increase as individuals got progressively older, suggesting that some type of mechanism kicks in to keep them in check.
Experiments suggested that once a person becomes elderly, certain immune cells called killer CD4+ T cells are responsible for keeping senescent cells from increasing. Indeed, higher numbers of killer CD4+ T cells in tissue samples were associated with reduced numbers of senescent cells in old skin.
When they assessed how killer CD4+ T cells keep senescent cells in check, the researchers found that aging skin cells express a protein, or antigen, produced by human cytomegalovirus, a pervasive herpesvirus that establishes lifelong latent infection in most humans without any symptoms. By expressing this protein, senescent cells become targets for attack by killer CD4+ T cells.
“Our study has revealed that immune responses to human cytomegalovirus contribute to maintaining the balance of aging organs,” says senior author Shawn Demehri, MD, PhD, director of the High Risk Skin Cancer Clinic at MGH and an associate professor of Dermatology at Harvard Medical School. “Most of us are infected with human cytomegalovirus, and our immune system has evolved to eliminate cells, including senescent cells, that upregulate the expression of cytomegalovirus antigens.”
These findings, which highlight a beneficial function of viruses living in our body, could have a variety of clinical applications. “Our research enables a new therapeutic approach to eliminate aging cells by boosting the anti-viral immune response,” says Demehri. “We are interested in utilizing the immune response to cytomegalovirus as a therapy to eliminate senescent cells in diseases like cancer, fibrosis and degenerative diseases.”
Demehri notes that the work may also lead to advances in cosmetic dermatology, for example in the development of new treatments to make skin look younger.
Co-authors include Tatsuya Hasegawa, Tomonori Oka, Heehwa G. Son, Valeria S. Oliver-García, Marjan Azin, Thomas M. Eisenhaure, David J. Lieb, and Nir Hacohen.
This study was supported by the Burroughs Wellcome Fund and Shiseido Co. Ltd.

According to the U.S. Centers for Disease Control, one out of every three adults in the United States has prediabetes, a condition marked by elevated blood sugar levels that could lead to the development of Type 2 diabetes. The good news is that, if detected early, prediabetes can be reversed through lifestyle changes such as improved diet and exercise. The bad news? Eight out of 10 Americans with prediabetes don’t know that they have it, putting them at increased risk of developing diabetes as well as disease complications that include heart disease, kidney failure and vision loss.
Current screening methods typically involve a visit to a health care facility for laboratory testing and/or the use of a portable glucometer for at-home testing, meaning access and cost may be barriers to more widespread screening. But researchers at the University of Washington may have found the sweet spot when it comes to increasing early detection of prediabetes. The team developed GlucoScreen, a new system that leverages the capacitive touch sensing capabilities of any smartphone to measure blood glucose levels without the need for a separate reader.
The researchers describe GlucoScreen in a new paper published March 28 in the Proceedings of the Association for Computing Machinery on Interactive, Mobile, Wearable and Ubiquitous Technologies.
The researchers’ results suggest GlucoScreen’s accuracy is comparable to that of standard glucometer testing. The team found the system to be accurate at the crucial threshold between a normal blood glucose level, at or below 99 mg/dL, and prediabetes, defined as a blood glucose level between 100 and 125 mg/dL. This approach could make glucose testing less costly and more accessible — particularly for one-time screening of a large population.
“In conventional screening a person applies a drop of blood to a test strip, where the blood reacts chemically with the enzymes on the strip. A glucometer is used to analyze that reaction and deliver a blood glucose reading,” said lead author Anandghan Waghmare, a UW doctoral student in the Paul G. Allen School of Computer Science & Engineering. “We took the same test strip and added inexpensive circuitry that communicates data generated by that reaction to any smartphone through simulated tapping on the screen. GlucoScreen then processes the data and displays the result right on the phone, alerting the person if they are at risk so they know to follow up with their physician.”
Specifically, the GlucoScreen test strip samples the amplitude of the electrochemical reaction that occurs when a blood sample mixes with enzymes five times each second.

The strip then transmits the amplitude data to the phone through a series of touches at variable speeds using a technique called “pulse-width modulation.” The term “pulse width” refers to the distance between peaks in the signal — in this case, the length between taps. Each pulse width represents a value along the curve. The greater the distance between taps for a particular value, the higher the amplitude associated with the electrochemical reaction on the strip.
“You communicate with your phone by tapping the screen with your finger,” Waghmare said. “That’s basically what the strip is doing, only instead of a single tap to produce a single action, it’s doing multiple taps at varying speeds. It’s comparable to how Morse code transmits information through tapping patterns.”
The advantage of this technique is that it does not require complicated electronic components. This minimizes the cost to manufacture the strip and the power required for it to operate compared to more conventional communication methods, like Bluetooth and WiFi. All data processing and computation occurs on the phone, which simplifies the strip and further reduces the cost.
The test strip also doesn’t need batteries. It uses photodiodes instead to draw what little power it needs from the phone’s flash.
The flash is automatically engaged by the GlucoScreen app, which walks the user through each step of the testing process. First, a user affixes each end of the test strip to the front and back of the phone as directed. Next, they prick their finger with a lancet, as they would in a conventional test, and apply a drop of blood to the biosensor attached to the test strip. After the data is transmitted from the strip to the phone, the app applies machine learning to analyze the data and calculate a blood glucose reading.

That stage of the process is similar to that performed on a commercial glucometer. What sets GlucoScreen apart, in addition to its novel touch technique, is its universality.
“Because we use the built-in capacitive touch screen that’s present in every smartphone, our solution can be easily adapted for widespread use. Additionally, our approach does not require low-level access to the capacitive touch data, so you don’t have to access the operating system to make GlucoScreen work,” said co-author Jason Hoffman, a UW doctoral student in the Allen School. “We’ve designed it to be ‘plug and play.’ You don’t need to root the phone — in fact, you don’t need to do anything with the phone, other than install the app. Whatever model you have, it will work off the shelf.”
The researchers evaluated their approach using a combination of in vitro and clinical testing. Due to the COVID-19 pandemic, they had to delay the latter until 2021 when, on a trip home to India, Waghmare connected with Dr. Shailesh Pitale at Dew Medicare and Trinity Hospital. Upon learning about the UW project, Dr. Pitale agreed to facilitate a clinical study involving 75 consenting patients who were already scheduled to have blood drawn for a laboratory blood glucose test. Using that laboratory test as the ground truth, Waghmare and the team evaluated GlucoScreen’s performance against that of a conventional strip and glucometer.
Given how common prediabetes and diabetes are globally, this type of technology has the potential to change clinical care, the researchers said.
“One of the barriers I see in my clinical practice is that many patients can’t afford to test themselves, as glucometers and their test strips are too expensive. And, it’s usually the people who most need their glucose tested who face the biggest barriers,” said co-author Dr. Matthew Thompson, UW professor of both family medicine in the UW School of Medicine and global health. “Given how many of my patients use smartphones now, a system like GlucoScreen could really transform our ability to screen and monitor people with prediabetes and even diabetes.”
GlucoScreen is presently a research prototype. Additional user-focused and clinical studies, along with alterations to how test strips are manufactured and packaged, would be required before the system could be made widely available, the team said.
But, the researchers added, the project demonstrates how we have only begun to tap into the potential of smartphones as a health screening tool.
“Now that we’ve shown we can build electrochemical assays that can work with a smartphone instead of a dedicated reader, you can imagine extending this approach to expand screening for other conditions,” said senior author Shwetak Patel, the Washington Research Foundation Entrepreneurship Endowed Professor in Computer Science & Engineering and Electrical & Computer Engineering at the UW.
Additional co-authors are Farshid Salemi Parizi, a former UW doctoral student in electrical and computer engineering who is now a senior machine learning engineer at OctoML, and Yuntao Wang, a research professor at Tsinghua University and former visiting professor at the Allen School. This research was funded in part by the Bill & Melinda Gates Foundation.

As tick season kicks in across the country, the executive director of the University of Massachusetts Amherst-based New England Center of Excellence in Vector-Borne Diseases (NEWVEC) and his team have completed research that offers a promising lead in the fight against Lyme disease.
The study, published recently in the journal Vector-borne and Zoonotic Diseases, demonstrates that the blood of the white-tailed deer kills the corkscrew-shaped bacterium that causes Lyme disease, a potentially debilitating illness. The Centers for Disease Control and Prevention (CDC) estimates that each year some 476,000 people are diagnosed with and treated for Lyme, the most common vector-borne disease in the U.S.
“Deer are vitally important to the survival of deer ticks, but they are not involved with transmitting the Lyme bacteria, Borrelia burgdorferi,” explains senior author Stephen Rich, professor of microbiology. “We’ve known for some time that ticks taken from white-tailed deer are not infected, and we speculated that something about the deer prevented those ticks from becoming infected. But until publication of our paper, no one had done the experiment to show that deer blood — specifically the serum component of white-tailed deer blood — kills Lyme.”
The results of the study may one day lead to new strategies and approaches for Lyme disease prevention and treatment, says lead author Patrick Pearson, a Ph.D. student in NEWVEC, whose upcoming doctoral examination focuses in part on this research.
“In these experiments we determined that white-tailed deer serum kills theLymebacterium. The next important question will be to understand exactly how deer blood kills Lyme bacteria,” Pearson says.
The research is one project of NEWVEC, which was funded by the CDC last year with a $10 million award to prevent and reduce tick- and mosquito-borne diseases in New England. NEWVEC aims to bring together academic communities, public health practitioners, residents and visitors across the Northeast, where Lyme infections are concentrated.

The Lyme disease bacterium is passed to juvenile blacklegged (Ixodes scapularis) deer ticks from mice the arthropods feed on. The infected ticks then pass the bacterium on to humans when they feed on people.
“We are the accidental host,” Rich says. “The ticks that bite us are actually looking for a deer because that’s where they breed. Without the deer, you don’t have ticks. But if you had only deer, you wouldn’t have any Lyme.”
To carry out their experiment, the researchers obtained blood serum from a semi-captive white-tailed deer herd at Auburn University in Alabama. The deer were believed to have no exposure to ticks and the bacteria that causes Lyme disease.
The researchers then grew the Lyme disease germ in test tubes and added the deer serum. “And lo and behold, it killed the bacteria,” Rich says. “Whatever it is in the deer that’s killing the germ is part of the innate immune system, a part of the immune system that precedes antibodies.”
Pearson adds, “The Lyme bacterium has proteins on its surface that protect it from the human innate immune system. Deer blood is somehow different such that Lyme bacteria are apparently unable to protect themselves from the innate immune system of white-tailed deer.”
The next research step is to determine the precise mechanisms in deer blood that kill the bacteria.
“We’d like to determine if it’s something we can induce in humans,” Rich says. “Or maybe we could use this somehow to our advantage to reduce the incidence of Lyme disease in the wild.”

White blood cells called neutrophils have an unappreciated role in eradicating solid tumors, according to a surprise discovery from a team led by Weill Cornell Medicine scientists.
In the study, published March 30 in Cell, the researchers investigated how a T cell-based immunotherapy was able to destroy melanoma tumors even though many of the tumor cells lacked the markers or “antigens” targeted by the T cells. They found that the T cells, in attacking the tumors, activated a swarm of neutrophils — which in turn killed the tumor cells that the T cells couldn’t eliminate. The findings could lead to new immunotherapies that harness this unexpected but potent antitumor immune response.
“We have tended to think of innate cells as immune cells that, at best, can help stimulate an initial T cell response to a tumor. In addition, many studies have shown that neutrophils support tumor progression, but here we reveal that they can have a critical role in eliminating and finishing off a tumor that would otherwise escape a T cell therapy,” said study co-senior author Dr. Taha Merghoub, deputy director of the Sandra and Edward Meyer Cancer Center, the Margaret and Herman Sokol Professor of Oncology Research and a professor of pharmacology at Weill Cornell Medicine, and co-director of the Ludwig Collaborative Laboratory.
“This work clearly shows us that the monolithic term ‘neutrophil’ needs to be more specific, based on the use of single-cell technology,” said co-senior author Dr. Jedd Wolchok, the Meyer Director of the Meyer Cancer Center and a professor of medicine at Weill Cornell Medicine, co-director of the Ludwig Collaborative Laboratory and an oncologist at NewYork-Presbyterian/Weill Cornell Medical Center. “In the past, this general term referred to a population of cells that were not thought to be helpful in controlling tumors. We now know that a subset of these cells is critical in optimizing engineered T cell therapies to overcome heterogeneity.”
Cancer immunotherapies, which harness or boost immune cells’ ability to attack malignant cells, have begun to revolutionize cancer treatment over the past decade. In some cases, these therapies have essentially cured advanced cancer patients who would have had no hope of survival otherwise. Yet for most cancers, immunotherapies are effective in only a minority of patients. In general, researchers still have much to learn about how anticancer immunotherapies work and how their effectiveness can be improved.
In the study, the researchers investigated an experimental immunotherapy that includes a drug to boost T cell activity and proliferation, plus T cells that have been engineered to recognize a melanoma-associated antigen. Tumors sometimes can evade an immunotherapy targeting a specific tumor antigen simply by ceasing to express that antigen — the tumor cells that don’t express the antigen are called “escape variants.” However, the researchers found that their boosted T cell therapy could eliminate melanomas, in standard mouse models, even when a large portion of the melanoma cells lacked the targeted antigen, Trp1.

Ultimately, they determined that the initial anti-tumor activity of the T cells against Trp1-expressing melanoma cells triggered a secondary tumor-killing response — from neutrophils. These white blood cells are best known as first-responders to infections and wounds. As members of the evolutionary older “innate” immune system, they do not target specific antigens in the way that T cells do. Yet the researchers concluded that the neutrophils summoned by their T-cell immunotherapy were indeed responsible for killing off the remaining, non-Trp1-expressing melanoma cells — at least in part by secreting the highly reactive molecule nitric oxide.
As part of the study, the researchers identified a characteristic gene expression pattern in the antitumor neutrophils, and found that in a widely used database on melanoma patients, the greater presence of this gene-expression “signature” in biopsied tumor samples was associated with better outcomes for patients.
The results were especially surprising because prior studies have shown that neutrophils around a tumor often act as allies of the tumor — the tumor co-opts them to help it survive and spread, which they do in part by suppressing other elements of antitumor immunity.
In any case, the new findings suggest that in the context of a strong immunotherapy that includes engineered T-cells targeting tumor antigens, and a general boosting of T-cell functions, neutrophils can play a significant antitumor role — in fact, an essential role in mopping up escape variant tumor cells that would otherwise keep the tumor alive.
“Conventional T cell-based therapies have been successful in treating cancers, but they are not as effective against heterogenous tumors, which have antigen escape variants that can be invisible to the immune system,” said Dr. Daniel Hirschhorn, an assistant professor of research in pharmacology at Weill Cornell Medicine. “It was incredibly surprising to discover that T cell-educated neutrophils can eliminate these ‘invisible’ tumor cells. This discovery highlights the importance of mobilizing multiple arms of the immune system in the fight against cancer.”
The researchers now are continuing to study these anti-tumor neutrophils, to determine how they can best be induced and directed — as cancer-fighters on their own, or as enhancers of other immunotherapies.
“I also hope that we can find a way to use measures of these antitumor neutrophils in tumor biopsies as biomarkers that help us choose the best therapies for patients,” Dr. Merghoub said.

A new study led by Worcester Polytechnic Institute (WPI) brings into sharper focus the structural details of the COVID-19 virus, revealing an elliptical shape that “breathes,” or changes shape, as it moves in the body. The discovery, which could lead to new antiviral therapies for the disease and quicker development of vaccines, is featured in the April edition of the peer-reviewed Cell Press structural biology journal Structure.
“This is critical knowledge we need to fight future pandemics,” said Dmitry Korkin, Harold L. Jurist ’61 and Heather E. Jurist Dean’s Professor of Computer Science and lead researcher on the project. “Understanding the SARS-COV-2 virus envelope should allow us to model the actual process of the virus attaching to the cell and apply this knowledge to our understanding of the therapies at the molecular level. For instance, how can the viral activity be inhibited by antiviral drugs? How much antiviral blocking is needed to prevent virus-to-host interaction? We don’t know. But this is the best thing we can do right now — to be able to simulate actual processes.”
Feeding genetic sequencing information and massive amounts of real-world data about the pandemic virus into a supercomputer in Texas, Korkin and his team, working in partnership with a group led by Siewert-Jan Marrink at the University of Groningen, Netherlands, produced a computational model of the virus’s envelope, or outer shell, in “near atomistic detail” that had until now been beyond the reach of even the most powerful microscopes and imaging techniques.
Essentially, the computer used structural bioinformatics and computational biophysics to create its own picture of what the SARS-COV-2 particle looks like. And that picture showed that the virus is more elliptical than spherical and can change its shape. Korkin said the work also led to a better understanding of the M proteins in particular: underappreciated and overlooked components of the virus’s envelope.
The M proteins form entities called dimers with a copy of each other, and play a role in the particle’s shape-shifting by keeping the structure flexible overall while providing a triangular mesh-like structure on the interior that makes it remarkably resilient, Korkin said. In contrast, on the exterior, the proteins assemble into mysterious filament-like structures that have puzzled scientists who have seen Korkin’s results, and will require further study.
Korkin said the structural model developed by the researchers expands what was already known about the envelope architecture of the SARS-COV-2 virus and previous SARS- and MERS-related outbreaks. The computational protocol used to create the model could also be applied to more rapidly model future coronaviruses, he said. A clearer picture of the virus’ structure could reveal crucial vulnerabilities.
“The envelope properties of SARS-COV-2 are likely to be similar to other coronaviruses,” he said. “Eventually, knowledge about the properties of coronavirus membrane proteins could lead to new therapies and vaccines for future viruses.”
The new findings published in Structure were three years in the making and built upon Korkin’s work in the early days of the pandemic to provide the first 3D roadmap of the virus, based on genetic sequence information from the first isolated strain in China.