Severe symptoms of COVID-19, leading often to death, are thought to result from the patient's own acute immune response rather than from damage inflicted directly by the virus. Immense research efforts are invested in figuring out how the virus manages to mount an effective invasion while throwing the immune system off course.

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A new study, published today in Nature, reveals a multipronged strategy that the virus employs to ensure its quick and efficient replication, while avoiding detection by the immune system. The joint labor of the research groups of Dr. Noam Stern-Ginossar at the Weizmann Institute of Science and Dr. Nir Paran and Dr. Tomer Israely of the Israel Institute for Biological, Chemical and Environmental Sciences, this study focused on understanding the molecular mechanisms at work during infection by SARS-CoV-2 at the cellular level.

During an infection, our cells are normally able to recognize that they're being invaded and quickly dispatch signaling molecules, which alert the immune system of the attack. With SARS-CoV-2 it was apparent early on that something was not working quite right – not only is the immune response delayed, enabling the virus to quickly replicate, unhindered, but once this response does occur it's often so severe that instead of fighting the virus it causes damage to its human host.

"Most of the research that has addressed this issue so far concentrated on specific viral proteins and characterized their functions. Yet not enough is known today about what is actually going on in the infected cells themselves," says Stern-Ginossar, of the Molecular Genetics Department. "So we infected cells with the virus and proceeded to assess how infection affects important biochemical processes in the cell, such as gene expression and protein synthesis."

When cells are infected by viruses, they start expressing a series of specific anti-viral genes – some act as first-line defenders and meet the virus head on in the cell itself, while others are secreted to the cell's environment, alerting neighboring cells and recruiting the immune system to combat the invader. At this point, both the cell and the virus race to the ribosomes, the cell's protein synthesis factories, which the virus itself lacks. What ensues is a battle between the two over this precious resource.

The new study has elucidated how SARS-CoV-2 gains the upper hand in this battle: It is able to quickly, in a matter of hours, take over the cell's protein-making machinery and at the same time to neutralize the cell's anti-viral signaling, both internal and external, delaying and muddling the immune response.

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The researchers showed that the virus is able to hack the cell's hardware, taking over its protein-synthesis machinery, by relying on three separate, yet complementary, tactics. The first tactic the virus uses is to reduce the cell's capacity for translating genes into proteins, meaning that less proteins are synthesized overall. The second tactic is that it actively degrades the cell's messenger RNAs (mRNA) – the molecules that carry instructions for making proteins from the DNA to the ribosomes – while its own mRNA transcripts remain protected. Finally, the study revealed that the virus is also able to prevent the export of mRNAs from the cell's nucleus, where they are synthesized, to the cell's main chamber, where they normally serve as the template for protein synthesis.

"By employing this three-way strategy, which appears to be unique to SARS-CoV-2, the virus is able to efficiently execute what we call 'host shutoff' – where the virus takes over the cell's protein-synthesis capacity," Stern-Ginossar explains. "In this way, messages from important anti-viral genes, which the cell rushes to produce upon infection, do not make it to the factory floor to be translated into active proteins, resulting in the delayed immune response we are seeing in the clinic." The good news is that this study was also successful in identifying the viral proteins involved in the process of host shutoff by SARS-CoV-2, which could spell new opportunities for developing effective COVID-19 treatments.

Study authors also included Yaara Finkel, Avi Gluck, Aharon Nachshon, Dr. Roni Winkler, Tal Fisher, Batsheva Rozman, Dr. Orel Mizrahi and Dr. Michal Schwartz, who are all members of Dr. Noam Stern-Ginossar's group; Dr. Yoav Lubelsky and Binyamin Zuckerman from Prof. Igor Ulitsky's group in the Department of Biological Regulation; Dr. Boris Slobodin from the Department of Biomolecular Sciences – as well as Dr. Yfat Yahalom-Ronen and Dr. Hadas Tamir from the Israel Institute for Biological, Chemical and Environmental Sciences.

Stern-Ginossar's research is supported by Skirball Chair in New Scientists; Knell Family Center for Microbiology; American Committee for the Weizmann Institute of Science 70th Anniversary Lab; Ben B. and Joyce E. Eisenberg Foundation; Maurice and Vivienne Wohl Biology Endowment; and Miel de Botton.

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Cancer immunotherapy may get a boost from an unexpected direction: bacteria residing within tumor cells. In a new study published in Nature, researchers at the Weizmann Institute of Science and their collaborators have discovered that the immune system "sees" these bacteria and shown they can be harnessed to provoke an immune reaction against the tumor. The study may also help clarify the connection between immunotherapy and the gut microbiome, explaining the findings of previous research that the microbiome affects the success of immunotherapy.

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Immunotherapy treatments of the past decade or so have dramatically improved recovery rates from certain cancers, particularly malignant melanoma; but in melanoma, they still work in only about 40% of the cases. Prof. Yardena Samuels of Weizmann's Molecular Cell Biology Department studies molecular "signposts" – protein fragments, or peptides, on the cell surface – that mark cancer cells as foreign and may therefore serve as potential added targets for immunotherapy. In the new study, she and colleagues extended their search for new cancer signposts to those bacteria known to colonize tumors.

Using methods developed by departmental colleague Dr. Ravid Straussman, who was one of the first to reveal the nature of the bacterial "guests" in cancer cells, Samuels and her team, led by Dr. Shelly Kalaora and Adi Nagler (joint co-first authors), analyzed tissue samples from 17 metastatic melanoma tumors derived from nine patients. They obtained bacterial genomic profiles of these tumors and then applied an approach known as HLA-peptidomics to identify tumor peptides that can be recognized by the immune system.

The research was conducted in collaboration with Dr. Jennifer A. Wargo of the University of Texas MD Anderson Cancer Center, Houston, Texas; Prof Scott N. Peterson of Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California; Prof Eytan Ruppin of the National Cancer Institute, USA; Prof Arie Admon of the Technion- Israel Institute of Technology and other scientists.

The HLA peptidomics analysis revealed nearly 300 peptides from 41 different bacteria on the surface of the melanoma cells. The crucial new finding was that the peptides were displayed on the cancer cell surfaces by HLA protein complexes – complexes that are present on the membranes of all cells in our body and play a role in regulating the immune response. One of the HLA's jobs is to sound an alarm about anything that is foreign by "presenting" foreign peptides to the immune system so that immune T cells can "see" them. "Using HLA peptidomics, we were able to reveal the HLA-presented peptides of the tumor in an unbiased manner," Kalaora says. "This method has already enabled us in the past to identify tumor antigens that have shown promising results in clinical trials."

It's unclear why cancer cells should perform a seemingly suicidal act of this sort: presenting bacterial peptides to the immune system, which can respond by destroying these cells. But whatever the reason, the fact that malignant cells do display these peptides in such a manner reveals an entirely new type of interaction between the immune system and the tumor.

This revelation supplies a potential explanation for how the gut microbiome affects immunotherapy. Some of the bacteria the team identified were known gut microbes. The presentation of the bacterial peptides on the surface of tumor cells is likely to play a role in the immune response, and future studies may establish which bacterial peptides enhance that immune response, enabling physicians to predict the success of immunotherapy and to tailor a personalized treatment accordingly.

Moreover, the fact that bacterial peptides on tumor cells are visible to the immune system can be exploited for enhancing immunotherapy. "Many of these peptides were shared by different metastases from the same patient or by tumors from different patients, which suggests that they have a therapeutic potential and a potent ability to produce immune activation," Nagler says.

In a series of continuing experiments, Samuels and colleagues incubated T cells from melanoma patients in a laboratory dish together with bacterial peptides derived from tumor cells of the same patient. The result: T cells were activated specifically toward the bacterial peptides.

"Our findings suggest that bacterial peptides presented on tumor cells can serve as potential targets for immunotherapy," Samuels said. "They may be exploited to help immune T cells recognize the tumor with greater precision, so that these cells can mount a better attack against the cancer. This approach can in the future be used in combination with existing immunotherapy drugs."

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Chronic stress could be one of the most prevalent conditions of our time. In the short term, stress causes our jaws or stomachs may clench; in the long term, stress can lead to metabolic disease and speed up diseases of aging, as well as leading to more serious psychological disorders.

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The physical manifestations of stress originate in the brain, and they move along a so-called "stress axis" that ends in the adrenal glands. These glands then produce the hormone cortisol. When the stress axis is continually activated, changes occur in the cells and organs along the way, and the continual production of cortisol then substantially contribute the symptoms of chronic stress.

The stress response axis starts with the hypothalamus in the brain, moves through the pituitary right next to the brain and then on to the adrenal glands near the kidneys. Scientists at the Weizmann Institute of Science in Israel and the Max Planck Institute of Psychiatry in Germany used new technology to view the entire stress axis as it has never before been seen. Their findings, published in the journal Science Advances, may be relevant to a number of stress-related diseases from anxiety and depression to metabolic syndrome and diabetes.

The new study, led by postdoctoral fellow Dr. Juan Pablo Lopez in the joint neurobiology lab of Prof. Alon Chen at the Weizmann Institute of Science and the Max Planck Institute of Psychiatry, made use of a relatively new technique that allows researchers to identify differences across all cell types in a tissue.

This method could be compared to identifying the individual fruits in a bowl of fruit salad rather than turning that fruit salad into a smoothie and then trying to identify the average characteristics of all the fruits together. But in this case, the task was more complex than separating the apples from oranges: Lopez and the team mapped the entire length of the stress axis, checking the activities of numerous single cells all along the route.

The researchers conducted this analysis on two sets of mice – one unstressed and one exposed to chronic stress.
In total, the team mapped 21,723 cells along the three points in that axis, and they compared their findings from the two sets of mice. They noted that as the stress message moved from one organ to the next, the gene expression in the cells and the tissues themselves underwent greater changes. The team found 66 genes that were altered between normal and stressed mice in the hypothalamus, 692 in the pituitaries and a whopping 922 in the adrenals. The adrenals are glands that can change their size visibly under chronic stress exposure, and it was here that the researchers noted the most significant alterations among the various cells.

The unprecedented resolution of the technique enabled the researchers to identify, for the first time, a subpopulation of adrenal cells that may play a crucial role in the stress response and adaptation. These were endocrine cells sitting in the outer layer, or adrenal cortex. Among other things, the team identified a gene, known as Abcb1b, and found it to be overexpressed in these cells under stress situations. This gene encodes a pump in the cell membrane that expels substances from the cell, and the scientists think it plays a role in the release of cortisol. "If extra stress hormones are created, the cell needs extra release valves to let those hormones go," says Lopez.

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Are the findings in mice relevant to humans? In collaboration with researchers in university-based hospitals in the UK, Germany, Switzerland and the US, the scientists obtained adrenal glands that had been removed from patients to relieve the symptoms of Cushing's disease. Though the disease is the result of a growth on the pituitary, the result can be identical to chronic stress – weight gain and metabolic syndrome, high blood pressure and depression or irritability – so in some cases it is treated by removing the adrenal glands, thereby reducing the patients' stress hormone load. Indeed, the cells in these patients' adrenals presented a similar picture to those of the mice in the chronic stress group.

The gene they had identified, Abcb1, was known to the researchers from previous studies into the genetics of depression. It had been found that this gene is polymorphic – it has several variants – and that at least one version is tied to a higher risk for depression. The group analyzed the expression of this variant in blood tests taken from a group of subjects who suffer from depression and who were subjected to temporary stress. They found that certain indeed affect the ways the adrenal glands deal with stress signals coming down the axis.

Chronic stress, of course, can ultimately affect every part of the body and open the door to numerous health issues. The new study, because it looks at the entire axis, on the one hand, and has mapped it down to the gene expression pattern of its individual cells, on the other, should provide a wealth of new information and insight into the mechanisms behind the stress axis.

"Most research in this field has focused on chronic stress patterns in the brain," says Chen. "In addition to presenting a possible new target for treating the diseases that arise from chronic stress, the findings of this study will open new directions for future research."

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