The Fondation Weizmann.be pour la science is a non-profit, private entity. Its aim is to promote the Weizmann Institute of Science in Belgium and to support its research projects via appropriate public relations activities as well as selective fund raising, in particular in the form of sponsorships, donations and legacies.
One of the Foundation’s regular activites is the sponsoring of promising students attending Belgian secondary schools, who qualify for participation in the annual 4 weeks International Scientific Summer School (ISSI) on the Weizmann Institute of Science campus, before continuing their tertiary education in science. This year two promising young women have been selected.
The Foundation is chaired by Mr Christian Hendboeg.
Mrs Diane Culer, Prof. Pierre Klees, Prof Maurice Sosnowski, Mr Paul de Schietere de Lophem, Mr Eric Hemeleers and Mr Roland Louis are directors.
The Belgian Foundation was founded in 2006, replacing the Belgian Committee, which had been established in 1973 by Prof. Georges Schnek, who also served as the first Secretary General until 1979. He was succeeded by Mr Louis Culer, who held this position for 20 years until 1999, followed by Prof. Marc van Montagu until June 2006.
Among the former Chairmen of the Committee were the former Belgian Prime Minister Theo Lefèvre (1973-1975), Prof. Piet de Somer, Rector of the “Katolieke Universiteit Leuven” (1975-1980) and Prof. Jean Brachet (1980-1972). Two Nobel Laureates, Prof. Christian de Duve and Prof. Ilya Prigogine, were members of the Academic Council.
High levels of defensive proteins offer protection against a hostile takeover by herpes viruses
“Let him who desires peace, prepare for war,” wrote the Roman author Vegetius in the 4th century CE. Our bodies, it seems, live by this dictum: Even in times of peace, some cells express high levels of defensive, antiviral proteins. A new Weizmann Institute of Science study reveals that the higher the routine levels of these proteins in a cell, the greater the chances of preventing a viral takeover.
When a virus enters a cell, it can gain control of the protein production mechanisms, forcing them to make multiple copies of itself. But infection might not lead to all-out war. While an active infection entails the virus killing the cell as it spreads its copies to other cells, at times a virus fails to take over the production mechanisms of the host cell, remaining latent within it, sometimes for decades. Herpes viruses, for example, are notorious for their ability to hide inside the body in a dormant state. What determines whether an active infection occurs, or the virus remains latent?
A team of researchers led by Dr. Michal Schwartz of Prof. Noam Stern-Ginossar’s lab in Weizmann’s Molecular Genetics Department addressed this question by focusing on human cytomegalovirus, a member of the herpes family that infects most of the population. Like other herpes viruses, cytomegalovirus awaits silently in the bodies of carriers, although it might cause an onset of symptomatic illness anytime later in life. The virus often raises its ugly head when a patient is immunosuppressed, following an organ transplant or chemotherapy. Pregnant women contracting the virus can pass it to the fetus, which sometimes suffers from serious illness as a result.
The scientists monitored the process of infection in two groups of immune cells – macrophages and their precursor cells – for 144 hours. At several points in time after infection, they sequenced RNA molecules from individual cells. Since RNA molecules carry the recipes for protein production, sequencing them revealed which proteins are produced, and in what quantities, at each stage of infection.
“As expected, shortly after infection the cells still only produced their own proteins,” says Schwartz. “However, a few hours later, the cells split into two groups. As some kept making their own proteins, others started assembling viral proteins, a step that initiates the multiplication of the viral genome and its spread throughout the body. We found this step to be irreversible: From the moment cells expressed just two initial viral proteins, we couldn’t stop the viral takeover.”
Searching for an explanation as to why the virus took over some cells but not others, the team examined the differences in proteins produced by each group of cells before and during infection. They discovered that the virus failed to take over cells that had already produced more antiviral defenses prior to infection. While the virus stayed as a latent guest within these cells, those with a lower routine production of defense proteins were open to a viral takeover.
“Latent viruses pose an existential threat to immunosuppressed patients and organ transplant recipients”
This local protein “shield,” produced not only by the attacked cell but throughout its environment, had long been recognized as the first line of defense against an ongoing viral infection. It was known to be generated in response to viral invasion, which prompts cells to secrete protein alerts called interferons. These warning signs, in turn, elicit antiviral protein production in nearby cells – a sort of code red to get ready for battle. Following the secretion of interferons, hundreds of genes for defense proteins are activated. The team’s finding showed that these defense proteins play a significant role even before the infection occurs and the warning signs are flagged.
The researchers believe that high levels of routine defense protein production might serve to immunize cells against a potential active infection. This idea suggests a possible solution to a previously unsolved mystery – why do cytomegaloviruses tend to accumulate in a latent state within bone marrow stem cells? Previous research by other scientists had found that stem cells routinely produce relatively high levels of defense proteins, compared to such mature immune cells as macrophages. These proteins’ newly discovered immunizing effect against active infection could explain why the viruses remain latent within the stem cells.
The scientists also discovered that mature macrophages, which had been thought to only play host to active infection, can harbor latent viral infection as well. This means that, contrary to the prevailing view, cells don’t fall into one of two categories – harboring either active or latent infection – but can be host to either, depending on their levels of defense protein production. In other words, various cell types in the body, formerly thought to be subject to active infection alone, might in fact form unknown reservoirs of latent, potentially harmful viruses. Discovering such reservoirs can lead to preventive treatments.
“Latent viruses pose an existential threat to immunosuppressed patients and organ transplant recipients,” says Stern-Ginossar. “A basic understanding of the mechanisms that determine whether an onset of illness occurs or the virus remains latent is crucial to developing effective treatments. If we find ways to activate or deactivate latent viruses on demand, it will allow us to better prepare patients prior to transplant or treatment. I am hopeful that the understanding of cellular self-defense mechanisms will find its way to effective solutions in the clinical field.”
How B-Cell Eaters Clean Their Plates
Parents tell their children to eat all the food on their plate, down to the last crumb. Certain cells within our lymph nodes, like obedient children, diligently follow this instruction. Although these cells – a subtype of macrophages, or “big eaters” – were first described in 1884 by German biologist Walther Flemming, their origin and mode of operation had until now remained a mystery. In a study published in the Journal of Experimental Medicine, a team of researchers headed by Prof. Ziv Shulman of the Weizmann Institute of Science has made discoveries that largely demystify the tingible body macrophages (TBMs). These tingible (i.e., stainable) cells turn out to eat every last morsel of another type of immune cell, to help protect our bodies from harm.
The cells bound for the dinner plate are the antibody-producing B cells, which reside in lymph nodes in readiness for invasion by pathogens such as viruses or bacteria. When an invasion occurs, they become active, divide rapidly and enter transient structures called germinal centers. These centers, situated in designated niches within lymph nodes, are “training camps” in which the B cells hone their defenses against a particular enemy. The B cells undergo an accelerated evolution of sorts, experiencing random mutations a million times faster than normal cells, a process that increases the binding capacity of the antibodies they produce. On rare occasions, however, other B cells may evolve to produce autoantibodies that target and harm the body’s own healthy tissues instead of pathogens.
By the end of the “training program,” cells that have undergone beneficial mutations survive for the most part, whereas those bearing ineffective or even harmful mutations commit “suicide” through a mechanism of programmed cell death. All these dead B cells, though inactive, can still give rise to harmful antibodies. How is this prevented?
That’s where the “big eaters” come into play. In the new study the team, led by research student Neta Gurwicz of Weizmann’s Systems Immunology Department, used genetically engineered mice to uncover the TBMs’ eating patterns and diet. Genes for two different fluorescent proteins were used to mark the “big eaters” in shiny green and the B cells in their training camps in bright red. As expected, a week after the mice were vaccinated so as to activate the B cells, training camp sites opened within lymph nodes, and B cells began to multiply, mutate and undergo selection. Through microsurgery, the scientists exposed lymph nodes in the mice’s knees and then attached an advanced microscope with a resolution of one millionth of a meter that enabled them to observe biological processes inside a living body.
“If we figure out how to make TBMs more effective at cleaning up the ‘training camps,’ we may have the key to the treatment of currently incurable diseases”
During this real-time broadcast, the team watched B cells moving constantly inside the training camp, while the “big eaters” stayed put in the vicinity, occasionally reaching out with octopus-like arms to grab dying B cells and engulf them. The TBMs did so at a fairly rapid rate: Each TBM captured a B cell around once every 10 minutes. Using a computer model, the scientists predicted that cleaning a single training camp of all its dying cells would require about 30 TBMs. In the live broadcast, an average of 25 TBMs were observed in each camp, indicating that the cleaning mechanism is indeed effective and thorough.
Lymph node recycle bins
Next, the researchers asked whether TBMs are choosy. Do they digest any B cell passing by, or do they prefer to snack on those within the training camps? The team discovered that when exposed to inactive B cells, TBMs did not “swallow the bait,” focusing solely on the mutating B cells.
Still, one question remained – where do TBMs come from?
To solve that riddle, the scientists replaced the mice’s immune system by first irradiating them, then introducing into their bone marrow progenitor blood cells carrying genes to color the future TBMs green. When training camps emerged in the lymph nodes in response to the vaccination, 75 percent of the nearby TBMs were green, revealing that their origin is indeed in the bone marrow. But the green cells only appeared around those training camps a few weeks after vaccination, raising the possibility that their journey included a stopover.
Cell feast streamed live: TBMs (green) swallow dying B cells (red) inside the lymph node “training camps”
The team repeated the experiment, this time shielding lymph nodes during the irradiation so that only the immune cells within these nodes would survive, while the others were eradicated. Unlike in the previous experiment, most of the TBMs lining up for the feast were not green; they developed from cells that were already in lymph nodes prior to vaccination. The researchers concluded that the TBMs develop from progenitor cells emerging from the bone marrow, but rather than stopping off, they go straight to lymph nodes and wait there for a while.
The scientists also discovered what causes progenitor cells to leave the bone marrow and enter lymph nodes. Five days after vaccination, when small concentrations of mutating B cells appeared in the training camps, substantial quantities of TBMs first emerged nearby. That suggested to the researchers that the timing of TBM arrival is a function of B cell training, and that the TBMs serve the particular purpose of cleaning up after what is a highly effective, but somewhat wasteful, immune system campaign.
Finally, the scientists asked when during the process that ends in their suicide the B cells are digested by TBMs. Surprisingly, they observed B cells being engulfed alive, undergoing their final last gasps inside the TBMs. This shows that the “big eaters” are not only “cleaning workers,” as previously thought, they also constitute a biological “recycle bin” that removes dying cells before they start breaking down, preventing harmful waste from scattering in the first place.
“Impaired TBM cleaning might cause the production of autoantibodies that would be aimed at the dead B cells but actually harm healthy tissues,” says Shulman. “This might be one of the causes for autoimmune diseases such as lupus. Basic understanding of the origin of TBMs and their modes of action could help pave the way for autoimmune disease treatments. If we figure out how to make TBMs more effective at cleaning up the ‘training camps,’ we may have the key to the treatment of currently incurable diseases.”
The following researchers also participated in the study: Dr. Liat Stoler-Barak of Weizmann’s Systems Immunology Department; and Niklas Schwan, Dr. Arnab Bandyopadhyay and Prof. Michael Meyer-Hermann of Braunschweig Integrated Centre of Systems Biology, Germany.
Weizmann Institute scientists have discovered how mutations in the BRCA genes, particularly prevalent among Ashkenazi Jews, lead to recruitment of cellular “assistants” in pancreatic cancer
Bullying, unfortunately, can be contagious. This applies not only at school or on the playground but also in the cellular neighborhood. That’s why in a new study, a team of researchers headed by Dr. Ruth Scherz-Shouval of the Weizmann Institute of Science focused not only on the cancer cells’ “bullying” behavior but also on its deleterious effects on the cells in the tumor’s surrounding microenvironment. These nonmalignant cells can help the body fight cancer, but sometimes they actually undermine this fight, becoming collaborators of the cancer cells. In the study, the scientists reveal how mutations in the BRCA genes, notorious for their role in breast and ovarian cancer, adversely affect a major subset of cells in the microenvironment of pancreatic cancer, impairing the body’s anticancer immune response.
The BRCA genes, in their normal form, play a significant role in cellular mechanisms that repair damaged DNA, but some people are born with a BRCA gene containing small changes (mutations) that disrupt its function. Although these mutations – particularly common among Ashkenazi Jews – are most known to women undergoing preventive screening for breast and ovarian cancer, they have been shown to increase the risk of cancer in men also, including tumors of the pancreas and prostate. Yet, awareness of this risk and the testing rate for BRCA mutations remain low among men.
The researchers conducted the new study on pancreatic ductal adenocarcinoma, a common and particularly aggressive type of pancreatic cancer that is still largely incurable. Only 10 percent of those diagnosed with it survive more than five years after diagnosis. Previous studies had shown that in this malignancy, cancer cells succeed in rewiring and even changing the structure and function of certain cells, called fibroblasts, in their microenvironment. Fibroblasts, which form the scaffolding holding cells in place, are basic components of every organ in our body. In pancreatic cancer, they can account for up to 90 percent of the tumor tissue. Once these cells cross over to the cancer’s side, they are reprogrammed into different subpopulations of cancer-associated fibroblasts. However, it is still largely unknown whether different cancer-related mutations, such as those in the BRCA genes, lead to different types of fibroblast reprogramming.
In an attempt to find the answer, researchers – led by Drs. Lee Shaashua, Aviad Ben-Shmuel and Meirav Pevsner-Fischer from Scherz-Shouval’s group in Weizmann’s Biomolecular Sciences Department – sought to establish whether BRCA mutations produce a unique negative effect on the fibroblasts in the tumor microenvironment of pancreatic cancer. In collaboration with Memorial Sloan Kettering Cancer Center in New York, they used innovative research methods to map and compare fibroblasts in pancreatic tumor samples containing cancerous cells with and without BRCA mutations.
Although these mutations are most known to women undergoing preventive screening for breast and ovarian cancer, they have been shown to increase the risk of cancer in men also
The scientists found that these two types of tumors had significant differences in the composition of their fibroblast subpopulations. In particular, they discovered that pancreatic tumors with BRCA mutations contain a relatively large subpopulation of certain fibroblasts – those containing the protein clusterin. This chaperone protein, which helps other cellular proteins function properly, had been found in past studies to contribute to the development of pancreatic cancer tumors.
Next, using cell culture and mouse models of cancer, the researchers silenced a BRCA gene in cancer cells, so as to mimic the mutation-induced loss of its function. These experiments revealed how BRCA mutations trigger a change in adjacent fibroblasts’ composition, even though the fibroblasts do not themselves have the mutation. It turned out that the culprit, responsible for the increased proportion of clusterin-expressing fibroblasts, is the HSF1 protein. In healthy cells this protein is activated in response to stress; in previous studies, including those conducted in Scherz-Shouval’s lab, it had been found to play a role in turning fibroblasts into cancer-assisting cells.
In further experiments, the researchers discovered that BRCA silencing in cancer cells induced a shift in the function of adjacent fibroblasts, causing them to start suppressing the immune system’s T cells. The researchers also identified a structural change in the fibers produced by the fibroblasts: In tumors with an active, unmutated BRCA gene, fibroblasts generated tough fibers forming a dense meshwork, whereas in tumors lacking BRCA activity, fibroblasts produced branching and softer fibers.
These findings suggest that in pancreatic tumors harboring BRCA mutations, the action of fibroblasts as producers of fibers for the intercellular environment is significantly reduced. Instead, they act as immune response suppressors, thus contributing to the malignant tumors’ development.
Blazing the trail for new therapies
All the cells of our body operate in accordance with the same genetic code, but this code is expressed in an utterly different manner in different cell types, tissues and organs. The differences between the body’s various cells are due to changes and additions of modifications to the DNA. The modifications function as punctuation marks enabling the cell to read the code correctly and produce proteins accordingly. These marks determine, for example, whether to increase production of a certain protein (perhaps similar to the role of an exclamation mark) or whether to even read a certain gene at all. Such changes and additions to DNA are being studied closely in a field called epigenetics (Greek for “above genetics”).
The differences between the body’s various cells are due to changes and additions of modifications to the DNA. The modifications function as punctuation marks enabling the cell to read the code correctly
In another study by Scherz-Shouval’s lab, the scientists focused on an additional aspect of fibroblast conversion into “bullies”: epigenetic mechanisms employed by cancer cells for the rewiring of fibroblasts. In this study, led by Coral Halperin from Scherz-Shouval’s lab, in collaboration with Dr. Joschka Hey from Prof. Christoph Plass’s lab at the German Cancer Research Center (DKFZ), the team showed, in mouse models of breast cancer, that cancer cells induce epigenetic alterations in normal fibroblasts. As a result, unlike what happens in healthy tissue, these fibroblasts change their expression of certain genes and produce cancer-assisting proteins. The researchers also found a correlation between these changes and an elevation in the levels of a protein called RUNX1: Its production also increased in fibroblasts of cancer patients, and its activation could be responsible for the epigenetic alterations.
“The treatment of cancer has been revolutionized in recent years with the introduction of immunotherapy – drugs that recruit the immune system in a targeted attack on cancer cells,” says Scherz-Shouval. “Hopefully, the knowledge that we and other researchers have gathered – including the identification of immune-response-suppressing fibroblast subtypes, and of the proteins involved in turning fibroblasts into cancer promoters – can be harnessed for developing new drugs. Such drugs, alongside immunotherapeutic treatments, would effectively target not only cancer cells, but also their collaborators.”
One in 400 people among the general population – and 1 in 40 Ashkenazi Jews – is born with mutations in the BRCA genes that increase the risk of several cancer types.
The following researchers at the Weizmann Institute of Science also participated in the study of changes in the microenvironment of pancreatic cancer: Dr. Gil Friedman, Oshrat Levi-Galibov, Debra Barki, Dr. Reinat Nevo, Yaniv Stein, Chen Lior, Shimrit Mayer, Roni Stok, Hend Bishara and Rawand Hamodi from the Biomolecular Sciences Department. Other collaborators included Subhiksha Nandakumar, Dr. Nikolaus Schultz, Dr. William R. Jarnagin, Dr. Nicolas Lecomte and Dr. Christine A. Iacobuzio-Donahue of Memorial Sloan Kettering Cancer Center, New York; Dr. Lauren E. Brown, Dr. Wenhan Zhang and Prof. John A. Porco Jr. of Boston University; Dr. Han Sang Kim, Dr. Linda Bojmar and Prof. David Lyden of Weill Cornell Medicine, New York; Prof. Ephrat Levy-Lahad of Shaare Zedek Medical Center and The Hebrew University of Jerusalem; Dr. Talia Golan of Sheba Medical Center and Tel Aviv University; Prof. David A. Tuveson of Cold Spring Harbor Laboratory, New York; and Prof. David Kelsen of Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York.
Also involved in the epigenetic study in breast cancer at the German Cancer Research Center in Heidelberg were Dr. Dieter Weichenhan, Dr. Pavlo Lutsik and Prof. Christoph Plass.
Changing the Channel: Study Sheds New Light on a Promising Antidepressant
Ketamine, a well-known anesthetic used in smaller doses as a party drug, was hailed as a “new hope for depression” in a Time magazine cover story in 2017. Two years later, the arrival of the first ketamine-based antidepressant – the nasal spray esketamine, made by Johnson & Johnson – was applauded as the most exciting development in the treatment of mood disorders in decades. Yet the U.S. Food and Drug Administration still limits the spray’s use. It is mainly given to depressed patients who have not been helped by other therapies – in part, because the new drug’s mechanism of action is insufficiently understood, leading to concerns over its safety.
Today, a study published in Neuron reveals new details about how ketamine works, paving the way toward the development of safe, effective treatments for depression. The research was conducted at the Weizmann Institute of Science in Rehovot, Israel, and at the Max Planck Institute of Psychiatry in Munich, Germany, in collaboration with the Helmholtz Zentrum, Munich.
Even though depression is on the rise in developed countries, taking a heavy toll in terms of human suffering and economic loss, there have been no major breakthroughs in the treatment of depression since the 1987 approval of the most famous antidepressant of all time, Prozac. Meanwhile, existing drugs bring no relief to about a third of depressed patients. Even when the drugs do work, they take four to eight weeks to take effect, a delay that can prove fatal in suicidal cases. That’s precisely the reason for much of the excitement over ketamine-based therapies: They make people feel better within hours. Their antidepressant action then lasts for days after the drug itself has cleared from the body. Evidently, it’s the body’s response to ketamine, rather than ketamine itself, that produces the desired effect, but the nature of this response has until now been unclear.
When scientists tried to clarify ketamine’s mechanism of action in previous studies, they examined its impact on gene expression in brain tissues, but not in individual brain cells. This approach can miss crucial differences between different cell types. Recent technological advances, however, have made it possible to assess gene expression at an unprecedented level of resolution: that of the single cell. These technologies were employed in the new study, conducted under the guidance of Prof. Alon Chen, former managing director of the Max Planck Institute of Psychiatry and current president of the Weizmann Institute of Science.
“In-depth knowledge of how antidepressants work might lead to a better understanding of depression and help improve existing treatments”
In this study, researchers led by Dr. Juan Pablo Lopez mapped out gene expression in thousands of individual neurons in the brains of mice that had been given a dose of ketamine. These neurons belong to networks that convey their signals by means of the neurotransmitter glutamate. Ketamine had been known since the 1990s to produce its effects by acting on such neurons – this in contrast to older antidepressants, which mainly affect neurons influenced by serotonin. But since ketamine’s effect persists long after it leaves the body, its action could not be explained by mere blockage of glutamate receptors on the surfaces of neurons. “We wanted to clarify the molecular cascade that is triggered by ketamine, leading to its sustained antidepressant effects,” Lopez says.
To this end, the scientists focused on the ventral hippocampus, a brain region that in previous studies had been associated with the antidepressant effects of ketamine. After mapping out gene expression in cells from this area of the mouse brain, the researchers identified a subpopulation of neurons with a characteristic genetic signature. Ketamine had increased these neurons’ expression of a gene called Kcnq2, which encodes a potassium channel – that is, a tunnel that opens up in the cell membrane, enabling the passage of potassium ions. Potassium channels play a central role in the life of neurons, maintaining their stability and preventing their excessive firing. In a series of elaborate experiments on the molecular and cellular levels, which included electrophysiological, pharmacological, behavioral and functional studies, the scientists confirmed their major finding: Ketamine exerts its lasting antidepressant effect by enhancing the Kcnq2 potassium channels in a certain subtype of glutamate-sensitive neurons.
“In the past, other researchers used whole tissue samples, which are composed of different cell types, so ketamine’s effects on specific cell types were averaged out,” Lopez explains.
The researchers then tested ketamine’s effects in combination with an epilepsy drug, retigabine, known to activate potassium channels in the brain. When the drugs were given together, ketamine’s antidepressant effects were significantly enhanced. “A single dose of retigabine was enough to amplify and prolong ketamine’s antidepressant action in mice,” Lopez says. “Not only that, ketamine produced the same benefits when given in smaller doses than usual, which may help reduce its unwanted side effects.” Since both drugs already have FDA approval, the way is open toward testing their combined action in humans.
According to the World Health Organization, depression afflicts nearly 300 million people worldwide; more than 700,000 people commit suicide every year. Yet despite decades of research, much remains to be learned about the neuronal mechanisms underlying depression and the ways of manipulating those mechanisms with drugs.
By revealing a new mechanism of ketamine’s action, the study may make it possible to expand the use ketamine-based drugs. This, in turn, might help these drugs fully deliver on their promise of providing new hope for depression.
“In-depth knowledge of how antidepressants work might lead to a better understanding of depression and help improve existing treatments,” Chen sums up.
Prof. Chen’s research is supported by the Ruhman Family Laboratory for Research in the Neurobiology of Stress and the Licht Family. He is the incumbent of the Vera and John Schwartz Professorial Chair in Neurobiology.
A Matter of Survival: How the Immune System Sets Priorities
When a second infection follows on the heels of a first, the two arms of our immune system may clash
Even after prevailing over a viral infection, our immune system stays active, protecting us from any lingering viruses or recurring disease. But what happens if we pick up a bacterial infection – say, salmonella food poisoning from take-away chicken soup – while recovering from flu or COVID-19? A new study at the Weizmann Institute of Science published today in Immunity, shows that in such cases, the immune system has a clever way of setting priorities, one that might be exploited for the development of future therapies against autoimmune diseases.
This prioritizing involves the two arms of immunity: innate and adaptive. Innate immunity, the body’s first line of defense, springs into action as soon as the immune system senses an invasion by viruses, bacteria or other pathogens, deploying its cells and biochemicals in a broad offensive to neutralize the invaders. Adaptive immunity, on the other hand, may take several days to roll out its weapons: dedicated cells, as well as antibodies that are tailored to bind to different invaders with exquisite precision. The antibodies stay around for months or even years, offering long-lasting security.
This means that innate and adaptive immunity generally come to the fore at different stages of an infection. But when one infection is followed by another – for example, when a person overcoming a flu virus comes down with a bacterial infection such as salmonella – the two arms are forced to go into high gear at the same time: Innate immunity starts fighting the bacteria while adaptive immunity is still busy making antibodies against the flu virus.
A team headed by Prof. Ziv Shulman of Weizmann’s Immunology Department set out to learn how the two arms of immunity interact during such an overlap. In a study using mice, led by PhD student Adi Biram, they found that the interaction ends in a clash: Infection with salmonella interferes with the manufacture of antibodies against the flu. In other words, when faced with a lethal threat, the immune system shuts down mechanisms needed for long-term protection, dealing instead with the more urgent danger.
The researchers revealed that salmonella doesn’t produce this effect directly. Rather, when it infects lymph nodes, it sets off an alarm that reaches as far as the bone marrow, priming innate immunity cells called monocytes to rapidly leave the marrow in order to fight the bacteria. These monocytes flood the lymph nodes en masse, from there launching an attack on the salmonella. But in the process, as a result of their antimicrobial activity, these cells alter the environment within the lymph nodes, releasing various chemicals and causing a local oxygen shortage.
“It’s an either/or situation – when you are fighting life-threatening bacteria, you can’t be bothered with long-lasting immunity”
Most immune cells adapt to this shortage by changing their metabolism, shifting to burning glucose for energy instead of oxygen. But for a subset of B cells that reside in the lymph nodes in microscopic structures called germinal centers, an oxygen shortage proves fatal: Unable to adapt their metabolism, these B cells choke and die. This is precisely the subset of cells that plays a key role in adaptive immunity, generating antibodies having the best possible fit against the invading pathogen. The death of these cells puts an end to the production of antibodies required for long-lasting protection against the viral infection.
“It’s an either/or situation – when you are fighting life-threatening bacteria, you can’t be bothered with long-lasting immunity,” Shulman explains. “Destroying the salmonella gets priority because it’s a matter of survival.”
The study’s findings may have applications in various areas of immunology. Currently, certain bacterial proteins are sometimes added to vaccines in order to enhance their effectiveness, but the study suggests that such additions might backfire, harming antibody production. Moreover, if confirmed in humans, the new findings might lead to a new type of therapy for autoimmune diseases caused by the mistaken production of antibodies, for example, rheumatoid arthritis and lupus. Such a therapy would harness bone marrow monocytes to stop the production of disease-causing antibodies.
Also taking part in the study were Jingjing Liu, Dr. Hadas Hezroni, Dr. Natalia Davidzohn, Dr. Dominik Schmiedel, Dr. Eman Khatib-Massalha, Montaser Haddad, Dr. Amalie Grenov, Prof. Tsvee Lapidot and Prof. Steffen Jung of the Immunology Department; Sacha Lebon, Dotan Hoffman and Dr. Roi Avraham of the Biological Regulation Department; Dr. Tomer Meir Salame of the Life Sciences Core Facilities Department; Dr. Nili Dezorella of the Chemical Research Support Department; Paula Abou Karam of Biomolecular Sciences Department; and Prof. Mats Bemark of the University of Gothenburg, Sweden.
90% of deaths that occurred during the 1918 influenza pandemic are thought to have resulted from secondary pneumococcal pneumonia. In a large study at Rabin Medical Center, secondary bacterial infections occured in 12.6% of patients with COVID-19 and in 8.7% of flu patients.
Prof. Ziv Shulman’s research is supported by the Moross Integrated Cancer Center; the Rising Tide Foundation; the Azrieli Foundation; the Ben B. and Joyce E. Eisenberg Foundation; the Wolfson Family Charitable Trust & Wolfson Foundation; Elie Hirschfeld and Dr. Sarah Schlesinger; and Miel de Botton.