Trillions of commensal microbes live on the mucosal and epidermal surfaces of the body and it is firmly established that this microbiome affects its host’s tolerance and sensitivity of the host to a variety of pathogens. However, host tolerance to infection with pathogens is not equally developed in all organisms. For example, it is known that the gut microbiome of mice protects more effectively against infection with certain pathogens, such as the bacterium Salmonella typhimurium, than the human gut microbiome.
This raises the interesting possibility that analyzing differences between host-microbiome interactions in humans and other species, such as mice, and pinpointing individual types of bacterial that either protect or sensitize against certain pathogens, could lead to entirely new types of therapeutic approaches. However, while the intestinal microbiome composition and its effect on host immune responses have been well investigated in mice, it is not possible to study how the microbiome interacts directly with the epithelial cells lining the intestine under highly defined conditions, and thereby uncover specific bacterial strains that can induce host-tolerance to infectious pathogens.
Now, a collaborative team led by Wyss Founding Director Donald Ingber, M.D., Ph.D. at Harvard’s Wyss Institute for Biologically Inspired Engineering and Dennis Kasper, M.D. at Harvard Medical School (HMS) has harnessed the Wyss’s microfluidic Organs-on-Chip (Organ Chip) technology to model the different anatomical sections of the mouse intestine and their symbiosis with a complex living microbiome in vitro. The researchers recapitulated the destructive effects of S. typhimurium on the intestinal epithelial surface in an engineered mouse Colon Chip, and in a comparative analysis of mouse and human microbiomes were able to confirm the commensal bacterium Enterococcus faecium contributes to host tolerance to S. typhimurium infection. The study is published in Frontiers in Cellular and Infection Microbiology.
The project was started under a DARPA-supported “Technologies for Host Resilience” (THoR) Project at the Wyss Institute, whose goal it was to uncover key contributions to tolerance to infection by studying differences observed in certain animal species and humans. Using a human Colon Chip, Ingber’s group had shown in a previous study how metabolites produced by microbes derived from mouse and human feces have different potential to impact susceptibility to infection with an enterohemorrhagic E. coli pathogen.
“Biomedical research strongly depends on animal models such as mice, which undoubtedly have tremendous benefits, but do not provide an opportunity to study normal and pathological processes within a particular organ, such as the intestine, close-up and in real-time. This important proof-of-concept study with Dennis Kasper’s group highlights that our engineered mouse Intestine Chip platform offers exactly this capability and provides the possibility to study host-microbiome interactions with microbiomes from different species under highly controllable conditions in vitro,” said Ingber. “Given the deep level of characterization of mouse immunology, this capability could greatly help advance the work of researchers who currently use these animals to do research on microbiome and host responses. It enables them to compare their results they obtain directly with human Intestine Chips in the future so that the focus can be on identifying features of host response that are most relevant for humans.” Ingber also is the Judah Folkman Professor of Vascular Biology at HMS and Boston Children’s Hospital, and Professor of Bioengineering at the Harvard John A. Paulson School of Engineering and Applied Sciences.
Engineering a mouse Intestine-on-Chip platform
In their new study, the team focused on the mouse intestinal tract. “It has traditionally been extremely difficult to model host-microbiome interactions outside any organism as many bacteria are strictly anaerobic and die in normal atmospheric oxygen conditions. Organ Chip technology can recreate these conditions, and it is much easier to obtain primary intestinal and immune cells from mice than having to rely on human biopsies,” said first-author Francesca Gazzaniga, Ph.D., a Postdoctoral Fellow who works between Ingber’s and Kasper’s groups and spear-headed the project.

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Gazzaniga and her colleagues isolated intestinal crypts from different regions of the mouse intestinal tract, including the duodenum, jejunum, ileum, and colon, took their cells through an intermediate “organoid” step in culture in which small tissue fragments form and grow, which they then seeded into one of two parallel microfluidically perfused channels of the Wyss’ Organ Chips to create region-specific Intestine Chips. The second independently perfused channel mimics the blood vasculature, and is separated from the first by a porous membrane that allows the exchange of nutrients, metabolites, and secreted molecules that intestinal epithelial cells use to communicate with vascular and immune cells.
Homing in on the pathogen
The team then honed in on S. typhimurium as a pathogen. First, they introduced the pathogen into the epithelial lumen of the engineered mouse Colon Chip and recapitulated the key features associated with the break-down of intestinal tissue integrity known from mouse studies, including the disruption of normally tight adhesions between neighboring epithelial cells, decreased production of mucus, a spike in secretion of a key inflammatory chemokine (the mouse homolog of human IL-8), and changes in epithelial gene expression. In parallel, they showed that the mouse Colon Chip supported the growth and viability of complex bacterial consortia normally present in mouse and human gut microbiomes.
Putting these capabilities together, the researchers compared the effects of specific mouse and human microbial consortia that had previously been maintained stably in the intestines of ‘gnotobiotic’ mice that were housed in germ-free conditions by the Kasper team. By collecting complex microbiomes from the stool of those mice, and then inoculating them into the Colon Chips, the researchers observed chip-to-chip variability in consortium composition, which enabled them to relate microbe composition to functional effects on the host epithelium. “Using 16s sequencing gave us a good sense of the microbial compositions of the two consortia, and high numbers of one individual species, Enterococcus faecium, generated by only one of them in the Colon Chip, allowed the intestinal tissue to better tolerate the infection,” said Gazzaniga. “This nicely confirmed past findings and validated our approach as a new discovery platform that we can now use to investigate the mechanisms that underlie these effects as well as the contribution of vital immune cell contributions to host-tolerance, as well as infectious processes involving other pathogens.”
“The mouse intestine on a chip technology provides a unique approach to understand the relationship between the gut microbiota, host immunity, and a microbial pathogen. This important interrelationship is challenging to study in the living animal because there are so many uncontrollable factors. The beauty of this system is that essentially all parameters you wish to study are controllable and can easily be monitored. This system is a very useful step forward,” said Kasper, who is the William Ellery Channing Professor of Medicine and Professor of Immunology at HMS.
The researchers believe that their comparative in vitro approach could uncover specific cross-talk between pathogens and commensal bacteria with intestinal epithelial and immune cells, and that identified tolerance-enhancing bacteria could be used in future therapies, which may circumvent the problem increasing antimicrobial resistance of pathogenic bacterial strains.

Exercise during pregnancy may let mothers significantly reduce their children’s chances of developing diabetes and other metabolic diseases later in life, new research suggests.
A study in lab mice has found that maternal exercise during pregnancy prevented the transmission of metabolic diseases from an obese parent — either mother or father — to child. If the finding holds true in humans, it will have “huge implications” for helping pregnant women ensure their children live the healthiest lives possible, the researchers report in a new scientific paper.
This means that one day soon, a woman’s first trip to the doctor after conceiving might include a prescription for an exercise program.
“Most of the chronic diseases that we talk about today are known to have a fetal origin. This is to say that the parents’ poor health conditions prior to and during pregnancy have negative consequences to the child, potentially through chemical modification of the genes,” said researcher Zhen Yan, PhD, a top exercise expert at the University of Virginia School of Medicine. “We were inspired by our previous mouse research implicating that regular aerobic exercise for an obese mother before and during pregnancy can protect the child from early onset of diabetes. In this study, we asked the questions, what if an obese mother exercises only during pregnancy, and what if the father is obese?”
Exercise and Pregnancy
Scientists have known that exercise during pregnancy helps lead to healthy babies, reducing the risk of pregnancy complications and premature delivery. But Yan, the director of the Center for Skeletal Muscle Research at UVA’s Robert M. Berne Cardiovascular Research Center, wanted to see if the benefits continued throughout the children’s lives. And his work, both previous and new, suggests it does.
To determine that, Yan and his collaborators studied lab mice and their offspring. Some of the adult mice were fed typical mouse chow before and during pregnancy, while other were fed a high-fat, high-calorie diet to simulate obesity. Some receiving the high-fat diet before mating had access to a voluntary running wheel only during pregnancy, where they could run all they liked, while others did not, meaning they remained sedentary.
The results were striking: Both mothers and fathers in the high-fat group could predispose their offspring to metabolic disorders. In particular, male offspring of the sedentary mothers on high-fat diets were much more likely to develop high blood sugar and other metabolic problems in adulthood.
To better understand what was happening, the researchers looked at the adult offspring’s metabolism and chemical (epigenetic) modification of DNA. They found there were significant differences in metabolic health and how active certain genes were among the different groups of offspring, suggesting that the negative effects of parental obesity, although different between the father and the mother, last throughout the life of the offspring.
The good news is that maternal exercise only during pregnancy prevented a host of “epigenetic” changes that affect the workings of the offspring’s genes, the researchers found. Maternal exercise, they determined, completely blocked the negative effects of either mother’s or father’s obesity on the offspring.
The results, they say, provide the first evidence that maternal exercise only during pregnancy can prevent the transmission of metabolic diseases from parent to child.
“The take-home message is that it is not too late to start to exercise if a mother finds herself pregnant. Regular exercise will not only benefit the pregnancy and labor but also the health of the baby for the long run,” Yan said. “This is more exciting evidence that regular exercise is probably the most promising intervention that will help us deter the pandemic of chronic diseases in the aging world, as it can disrupt the vicious cycle of parents-to-child transmission of diseases.”

#masthead-section-label, #masthead-bar-one { display: none }The Coronavirus OutbreakliveLatest UpdatesMaps and CasesRisk Near YouVaccine RolloutGuidelines After VaccinationAdvertisementContinue reading the main storySupported byContinue reading the main storyHow Have You Dealt With Grief During the Pandemic?Tell us the resources you used to help cope with loss during the past year. You may be contacted by a reporter for inclusion in an upcoming project.Credit…Getty ImagesMarch 15, 2021, 2:52 p.m. ETThere is no timetable for grief, but there are ways of coping with it during each emotional stage.If you experienced a loss during the pandemic, how did you address your feelings and work through them? Were there books, tools, therapeutic outlets or websites that you found particularly helpful? Did you surround yourself with other people experiencing something similar, or did you find solace in one-on-one conversations with a counselor?We want to hear about the things that brought you comfort so that we can offer similar suggestions to our readers, who may also be grieving. Please use the form below to share your insights.What resources were most helpful while grieving?

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Immigrants imprisoned in immigration facilities across the country face health conditions and often have chronic illnesses that would expose them to greater risk with COVID-19, a new University of California, Davis, study suggests.
“The research is clear: immigration detention is not only unnecessary for facilitating a just immigration system, but also causes extensive harm to detained people, perhaps especially to those facing chronic health conditions,” said the study’s lead author, Caitlin Patler, professor of sociology. “This is particularly alarming in the context of the COVID-19 pandemic. The government must act quickly to permanently reduce reliance on this overly punitive and systematically unjust practice.”
The study was published earlier this month in the Journal of Immigrant and Minority Health.
“Even beyond the context of the COVID-19 pandemic, immigration detention harms people’s health by disrupting the continuity of their medical care,” added the study’s co-author, Altaf Saadi, a neurologist at Massachusetts General Hospital and Harvard Medical School. “The vast majority of people have a stable place to stay and would be able to receive better health care if not detained.”
The report cites the May 2020 death of Carlos Ernesto Escobar Mejia, the first person in ICE custody to die from COVID-19. “Health and legal professional have raised alarm that many detainees may be similarly imperiled by COVID-19 infection [in detention],” authors wrote.
Researchers looked at health data of more than 500 people detained in 2013-14 by U.S. Immigration and Customs Enforcement, or ICE, at hundreds of facilities across California. This data is the only publicly available health information for ICE detainees. Researchers said the detainees’ health conditions are likely similar to a current population.
Of the individuals detained in 2013-14, at least 42 percent had at least one chronic condition, combined with other health issues, and additionally face disruption in care upon entering the facility.
The vast majority, or 95.6 percent, reported having access to stable housing in the country.
“Even one chronic condition can increase risk for severe consequences from COVID-19,” the authors said. One study of COVID-19 patients, they said, revealed that more than 80 percent had more than one underlying medical condition. These risks are heightened if health conditions are not adequately managed and there is disruption of pre-existing health care because they are incarcerated, researchers said.
.” ..Decision-makers must consider every available option to mandate release from the congregate setting of detention centers in which social distancing is almost impossible even under ideal conditions,” researchers concluded in their study. “Release can be easily facilitated through existing Alternatives to Detention (ATD) programs in which individuals can be released to their families and communities as they continue with their immigration legal proceedings.”
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Materials provided by University of California – Davis. Original written by Karen Nikos-Rose. Note: Content may be edited for style and length.

A cytokine “hurricane” centered in the lungs drives respiratory symptoms in patients with severe COVID-19, a new study by immunologists at Columbia University Vagelos College of Physicians and Surgeons suggests.
Two cytokines, CCL2 and CCL3, appear critical in luring immune cells, called monocytes, from the bloodstream into the lungs, where the cells launch an overaggressive attempt to clear the virus.
Targeting these specific cytokines with inhibitors may calm the immune reaction and prevent lung tissue damage. Currently, one drug that blocks immune responses to CCL2 is being studied in clinical trials of patients with severe COVID-19.
Survivors of severe COVID-19, the study also found, had a greater abundance of antiviral T cells in their lungs than patients who died, suggesting these T cells may be critical in helping patients control the virus and preventing a runaway immune response.
The study, published online March 12 in the journal Immunity, is one of the first to examine the immune response as it unfolds in real time inside the lungs and the bloodstream in patients who are hospitalized with severe COVID-19.
Treatments for Severe COVID-19 Needed
In patients with severe COVID-19, the lungs are damaged, and patients need supplemental oxygen. The risk of mortality is over 40%.

Researchers at Massachusetts General Hospital (MGH) have uncovered new clues that add to the growing understanding of how female mammals, including humans, “silence” one X chromosome. Their new study, published in Molecular Cell, demonstrates how certain proteins alter the “architecture” of the X chromosome, which contributes to its inactivation. Better understanding of X chromosome inactivation could help scientists figure out how to reverse the process, potentially leading to cures for devastating genetic disorders.
Female mammals have two copies of the X chromosome in all of their cells. Each X chromosome contains many genes, but only one of the pair can be active; if both X chromosomes expressed genes, the cell couldn’t survive. To prevent both X chromosomes from being active, female mammals have a mechanism that inactivates one of them during development. X chromosome inactivation is orchestrated by a noncoding form of RNA called Xist, which silences genes by spreading across the chromosome, recruiting other proteins (such as Polycomb repressive complexes) to complete the task.
Jeannie Lee, MD, PhD, an investigator in the Department of Molecular Biology at MGH and the paper’s senior author, has led pioneering research on X chromosome inactivation. She believes that understanding the phenomenon could lead to cures for congenital diseases known as X-linked disorders, which are caused by mutations in genes on the active X chromosome. “Our goal is to reactivate the inactive X chromosome, which carries a good copy of the gene,” says Lee. Doing so could have profound benefits for people with conditions such as Rett syndrome, a disorder brought on by a mutation in a gene called MECP2 that almost always occurs in girls and causes severe problems with language, learning, coordination and other brain functions. In theory, reactivating the X chromosome could cure Rett syndrome and other X-linked disorders.
In this study, Lee and Andrea Kriz, a PhD student and first author of the paper, were interested in understanding the role of clusters of proteins called cohesins in X inactivation. Cohesins are known to play a critical role in gene expression. Imagine a chromosome as a long piece of string with genes and their regulatory sequences being far apart, says Lee. For the gene to be turned “on” and do its job, such as producing a specific protein, it has to come in contact with its distant regulator. Chromosomes allow this to happen by forming a small loop that brings together the gene and regulator. Ring-shaped cohesins help these loops form and stabilize. When the gene’s work is done and it’s time to turn off, a scissor-like protein called WAPL snips it, causing the gene to disconnect from its regulator. An active chromosome has many of these loops, which are continually forming and dissociating (or separating).
These small loops, which are essential for gene expression, are relatively suppressed on an inactivated X chromosome. One reason, as Lee and her colleagues have already shown, is that Xist “evicts” most cohesins from the inactive X chromosome and that this cohesin depletion may be necessary to reorganize the shape and structure of the chromosome for silencing.
In the current study, Lee and Kriz used embryonic stem cells from female mice to find out what happens when cohesin or WAPL levels are manipulated during X chromosome inactivation by using protein-degradation technology. “We found that if cohesin levels build up too high, the X chromosome cannot inactivate properly,” says Lee. Normally, retaining cohesins (which are normally supposed to be evicted) prevented the X chromosome from folding into an inactive shape and gene silencing was affected. “You need a fine balance between eviction and retention of cohesins during X chromosome inactivation,” says Lee.
Next, the authors asked what happens when cohesin is manipulated in an active X chromosome. The short answer: It takes on some peculiar qualities of an inactivated X chromosome. First, when there is insufficient cohesin, the active X develops structures called “superloops” that are usually only seen on the inactive X. Second, when there is too much cohesin, the active X develops “megadomains,” which Lee calls two “big blobs,” and are also ordinarily unique to the inactive X. “The fact that we can confer some features of the inactive X chromosome onto the active X chromosome just by toggling cohesin levels is intriguing,” says Lee. She and her colleagues are trying to understand how and why that happens.
These findings suggests that shape and structure of the X chromosome play a vital role in allowing Xist to spread from one side to the other and achieve inactivation. “The more we learn about what’s important for silencing the X chromosome,” says Lee, “the more likely we’ll be to find ways to reactivate it and to treat conditions like Rett syndrome.”
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A home-based parenting programme to prevent childhood behaviour problems, which very unusually focuses on children when they are still toddlers and, in some cases, just 12 months old, has proven highly successful during its first public health trial.
The six-session programme involves providing carefully-prepared feedback to parents about how they can build on positive moments when playing and engaging with their child using video clips of everyday interactions, which are filmed by a health professional while visiting their home.
It was trialled with 300 families of children who had shown early signs of behaviour problems. Half of the families received the programme alongside routine healthcare support, while the other half received routine support alone. When assessed five months later, the children whose families had access to the video-feedback approach displayed significantly reduced behavioural problems compared with those whose families had not.
All of the children were aged just one or two: far younger than the age at which interventions for behaviour problems are normally available. The results suggest that providing tailored support for parents at this earlier stage, if their children show early signs of challenging behaviour — such as very frequent or intense tantrums, or aggressive behaviour — would significantly reduce the chances of those problems worsening.
Children with enduring behaviour problems often experience many other difficulties as they grow up: with physical and mental health, education, and relationships. Behaviour problems currently affect 5% to 10% of all children.
The trial — one of the first ever ‘real-world’ tests of an intervention for challenging behaviours in children who are so young — was carried out by health professionals at six NHS Trusts in England and funded by the National Institute for Health Research. It was part of a wider project called ‘Healthy Start, Happy Start’, which is testing the video-based approach, led by academics at the University of Cambridge and Imperial College London.

Researchers at the University of Gothenburg, Sweden, have now presented results that may change our basic view of how type 2 diabetes occurs. Their study indicates that free fatty acids (FFAs) in the blood trigger insulin release even at a normal blood-sugar level, without an overt uncompensated insulin resistance in fat cells. What is more, the researchers demonstrate the connection with obesity: the amount of FFAs largely depends on how many extra kilos of adipose tissue a person carries, but also on how the body adapt to the increased adiposity.
Worldwide, extensive research is underway to clarify exactly what happens in the body as type 2 diabetes progresses, and why obesity is such a huge risk factor for the disease. For almost 50 years, diabetes researchers have been discussing their version of the chicken-or-egg question: Which comes first — insulin resistance or elevated insulin levels? The dominant hypothesis has long been that the pancreas steps up its insulin production because the cells have already become insulin-resistant, and blood sugar then rises. However, the results now published in the journal EBioMedicine support the opposing idea: that it is the insulin that increases first.
Detailed investigations
The study indicates that high FFA levels in the blood after the overnight fast raise insulin production in the morning. FFAs have long been part of the main research equation for type 2 diabetes, but it is now proposed that they also have another role: in progression of the disease.
For the study, researchers compared metabolism in adipose (fat-storing) tissue among 27 carefully selected research subjects (nine of normal weight, nine with obesity and normal blood sugar, and nine with both obesity and progressed type 2 diabetes). For several days, they underwent extensive examinations in which they had samples taken under varying conditions. The researchers analyzed metabolism and gene expression in the participants’ subcutaneous fat, and the levels of blood sugar, insulin, and FFAs in their blood.
FFAs seem to trigger insulin production
The people with obesity but not diabetes proved to have the same, normal blood-sugar levels as the healthy individuals of normal weight.

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“Interestingly, the nondiabetics with obesity had elevated levels of both free fatty acids and insulin in their blood, and those levels were similar to or higher than the levels we were able to measure in blood from the participants with both obesity and type 2 diabetes,” says Emanuel Fryk, resident doctor specializing in general medicine and doctoral student at Sahlgrenska Academy, University of Gothenburg, who is one of the study’s first authors.
In collaboration with researchers at Uppsala University, he observed the same pattern in a population study based on blood samples taken from 500 people after an overnight fast.
“The fact that we saw a link between free fatty acids and insulin there too suggests that the fatty acids are connected with the insulin release, and contribute to increased insulin production on an empty stomach, when blood sugar hasn’t risen,” says Fryk, who nevertheless points out that the finding needs to be confirmed with more research.
Ongoing research
Free fatty acids are found naturally in the bloodstream and, like glycerol, are a product of the body’s fat metabolism. In the subjects, the amount of glycerol released proved to be broadly the same per kilo of body fat, regardless of whether they were of normal weight, had obesity alone, or also had type 2 diabetes.

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“Our hypothesis is that the free fatty acids increase in the blood because the adipose tissue can’t store the excess energy anymore. We believe, in that case, it could be an early sign of incipient type 2 diabetes. If our findings are confirmed when other research methods are used, there may be a chance that some specific fatty acids could be developed into biomarkers. But that’s a long way off,” Fryk says.
Lifestyle crucial
Diabetes is one of the most common diseases, with an estimated 500,000 people affected in Sweden. There are also a large number of undetected cases, since many with type 2 diabetes are not yet aware they are ill. Diabetics are at an increased risk for a number of serious conditions, such as cardiovascular disease (which may result in heart attacks and strokes).
“There are many factors that contribute to the progression of type 2 diabetes, but it’s our lifestyle that has, in absolute terms, the largest impact for most people. Our study provides another argument that the most important thing you can do to slow diabetes progression is to change your life style early in the progression of the disease, before blood glucose is elevated, Fryk says.

Researchers at the University of Illinois Chicago have discovered that heparanase, HPSE, a poorly understood protein, is a key regulator of cells’ innate defense mechanisms.
Innate defense responses are programmed cellular mechanisms that are triggered by various danger signals, which have been conserved in many species throughout evolution. These systems can be set into action by pathogens, such as viruses, bacteria and parasites, as well as by environmental toxins and dysfunctional cells that can accumulate in the body over time. A more thorough understanding of the commonalities and connections between these processes has the potential to generate multi-target therapy against a variety of human diseases.
In a multi-institution team led by Alex Agelidis, a UIC MD/Ph.D. dual degree medical student, and Dr. Deepak Shukla, the UIC Marion Schenk Professor of Ophthalmology and UIC professor of microbiology and immunology at the College of Medicine, researchers used a systems approach to track shifts in important cellular building blocks in cells and mice genetically engineered to lack HPSE.
In this collaborative multidisciplinary study, Agelidis and coauthors show for the first time that HPSE acts as a cellular crossroads between antiviral immunity, proliferative signals and cell death.
“HPSE has been long known to drive late-stage inflammatory diseases yet it was once thought that this was primarily due to enzymatic activity of the protein breaking down heparan sulfate, a sugar molecule present in chains on the surface of virtually all cells,” Agelidis said.
While a major focus of the study was on identifying mechanisms of pathogenesis of herpes simplex virus (HSV-1), their work has broad implications for the treatment of diseases involving dysregulation of HPSE, including cancer, atherosclerosis and autoimmune disorders.

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When SARS-CoV-2, the virus that causes COVID-19, infects a human cell, it quickly begins to replicate by seizing the cell’s existing metabolic machinery. The infected cells churn out thousands of viral genomes and proteins while halting the production of their own resources. Researchers from Brigham and Women’s Hospital, Massachusetts General Hospital (MGH), and the Broad Institute, studying cultured cells shortly after infecting them with the virus, now have more insight into the metabolic pathways co-opted by the virus. The findings, published in Nature Communications, highlight the potential therapeutic benefit of drugs such as methotrexate, which inhibit folate and one-carbon metabolic pathways appropriated by the virus.
“One of the things we’re lacking in this pandemic is a pill that can be taken orally, as a prophylactic agent, before someone is hospitalized or even before they’re infected,” said corresponding author Benjamin Gewurz, MD, PhD, of the Division of Infectious Diseases. “Monoclonal antibodies have a lot of promise but need to be given intravenously. Blocking the metabolism pathways that viruses rely on to replicate could be a new strategy for treating patients at an early timepoint.”
To identify which metabolic pathways to target, the researchers obtained samples of the virus and cultivated them in a highly protected facility called a BSL-3 laboratory, located at the Broad Institute. They then paired up with the laboratory of co-senior author Vamsi Mootha, MD, of MGH, to apply mass spectrometry approaches to identify the resources being consumed and produced by healthy cells and infected cells. They studied the infected cells at an “eclipse point,” eight hours after infection, when the virus has begun manufacturing its RNA and proteins but has not yet exerted a serious effect on host cell growth and survival.
In analyzing the amino acids and thousands of chemical metabolites produced by the cells, the researchers observed that infected cells had depleted stores of glucose and folate. They demonstrated that the SARS-CoV-2 virus diverts building blocks from glucose production to the assembly of purine bases, which are necessary for creating large amounts of viral RNA. Additionally, they found that the 1-carbon pathway used to metabolize folate was hyperactive, thus supplying the virus with more carbon groups for making bases for DNA and RNA.
Drugs that inhibit folate metabolism, like methotrexate, are often used to treat autoimmune conditions like arthritis and could be therapeutic candidates for COVID-19. Methotrexate is currently being assessed as a treatment for the inflammation that accompanies more advanced COVID-19 infections, but the researchers suggest that it could also be beneficial early on. Their study also found that it could offer a synergistic effect when administered with the anti-viral drug remdesivir. Methotrexate’s immune-suppressing properties could make its proper administration as a prophylactic challenging, however. Researchers would need to determine how to maximize the drug’s antiviral effects without significantly compromising a patient’s natural immune response.
Still, Gewurz points out that oral antivirals are an important addition to an arsenal of therapies for COVID-19, serving both as an immediate treatment for infection as well as a defense against new variants and other coronaviruses.
“We’re hoping that, ultimately, we can find a way of preventing viruses from using cells’ metabolism pathways to replicate themselves because that could limit the ability of viruses to evolve resistance,” Gewurz said. “We’re starting to see new viral variants, and we’re hoping that we can stay ahead of that — treating patients before the virus has the chance to make copies of itself that could become resistant to antibodies.”
This work was supported by the National Institutes of Health (R01 AI137337, R01 CA228700, R35 GM122455), EMBO (ALTF 486-2018), a Burroughs Wellcome Career Award in Medical Sciences, the Howard Hughes Medical Institute and MassCPR. Gewurz and Mootha are listed as inventors on a patent application filed by the Broad Institute based on results from this manuscript.
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