How viruses affect the immune system

Fighting infections depends on bodies' capacity to quickly recognize infected cells and destroy them, a job done by a class of immune cells known as CD8+ T cells. These soldiers get some of their orders from chemical mediators known as cytokines that make them more or less responsive to outside threats. In most cases, CD8+ T cells quickly recognize and destroy infected cells to prevent the infection from spreading.

When it comes to viruses that lead to chronic infection, immune cells receive the wrong set of marching orders, which makes them less responsive," says Martin Richer, an assistant professor at McGill's Department of Microbiology & Immunology and senior author of the study. The research, conducted in Richer's lab by graduate student Logan Smith, revealed that certain viruses persist by driving the production of a cytokine that leads to modification of glycoproteins on the surface of the CD8+ T cells, making the cells less functional.

That maneuver creates time for the pathogen to outpace the immune response and establish a chronic infection. Importantly, this pathway can be targeted to restore some functionality to the T cells and enhance the capacity to control infection. The discovery of this regulatory pathway could help identify new therapeutic targets for a variety of diseases.
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Grape-derived compounds may promote resilience against depression

Scientists from the Icahn School of Medicine at Mount Sinai describe an extensive analysis of novel grape-derived compounds, dihydrocaffeic acid (DHCA) and malvidin-3'-O-glucoside (Mal-gluc), which might be developed as therapeutic agents for the treatment of depression. The study results indicate that these natural compounds may attenuate depression by targeting newly discovered underlying mechanisms of the disease.

Conventional pharmacological treatments are estimated to produce temporary remission in less than 50 percent of patients, and they are often associated with severe adverse effects. Thus, there is an urgent need for a wider spectrum of novel therapeutics.

Depression is associated with a multitude of pathological processes, including inflammation of the peripheral immune system, a set of biological structures and processes in the lymph nodes and other tissues that protect against disease and abnormalities involving synapses, the structures that permit neurons to pass an electrical or chemical signal to other neurons.

However, currently available antidepressants are largely restricted to targeting the systems that regulate serotonin, dopamine, and other related neurotransmitters, and these treatments do not specifically address inflammation and synaptic maladaptations that are now known to be associated with MDD.

Previous research has found that grape-derived polyphenols have some efficacy in modulating aspects of depression, yet the mechanisms of action had largely remained unknown until now. The new study, led by Giulio Maria Pasinetti, PhD, Saunders Professor of Neurology, and a team of investigators from the Center for Integrative Molecular Neuroresilience at the Icahn School of Medicine at Mount Sinai, found that a bioactive dietary polyphenol preparation-a combination of three grape-derived polyphenol products, including a select Concord grape juice, a select grape seed extract, and trans-resveratrol was effective in promoting resilience against stress-induced depression in mice.

Specifically, researchers found that DHCA and Mal-gluc can promote resilience in mouse models of depression by modulating inflammation and synaptic plasticity, respectively. DHCA reduces interleukin 6 (IL-6), a pro-inflammatory substance secreted by T cells and macrophages to stimulate immune response, by epigenetically modulating the non-coding sequence of the IL-6 gene. Mal-gluc modulates histone acetylation of the Rac1 gene and allows transcription activators to access the DNA for increased transcription in the brain, which influences the expression of genes responsible for synaptic plasticity.

Researchers also demonstrated that DHCA/Mal-gluc treatment was effective in attenuating depression-like phenotypes in a mouse model of increased systemic inflammation induced by transplantation of cells from the bone marrow of stress-susceptible mice. The research shows that combination treatment with the two compounds can promote resilience against stress-mediated depression-like phenotypes by modulating systemic inflammatory responses and brain synaptic plasticity in a mouse model of depression.

The Mount Sinai study provides novel preclinical evidence supporting the targeting of multiple key disease mechanisms through DNA epigenetic modification for the treatment of depression. This study strongly supports the need to test and identify novel compounds that target alternative pathologic mechanisms, such as inflammation and synaptic maladaptation, for individuals who are resistant to currently available treatment.

Using combination treatment of DHCA and Mal-gluc to simultaneously inhibit peripheral inflammation and modulate synaptic plasticity in the brain works synergistically to optimize resilience against chronic stress-induced depression-like phenotypes. The discovery of these new, natural grape-derived polyphenol compounds targeting cellular and molecular pathways associated with inflammation may provide an effective way to treat a subset of people with depression and anxiety, a condition that affects so many people.
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Therapeutic for pancreatic cancer

In most pancreatic cancer patients, the diagnosis occurs when the disease is already advanced, and currently, there is no effective treatment. A group of researchers from the Spanish National Cancer Research Centre (CNIO) may have found a new therapeutic approach.

One of the characteristics of pancreatic cancer is that the tumour cells are embedded in the stroma, which represents 90 percent of the tumour mass and which seems to form a barrier (physical and chemical) hindering treatment with inhibitors, chemotherapy and immunotherapy.

Researchers focused their work on identifying a stromal cell population that fosters tumour growth, to later discover why they have this capacity and reverse it. The strategy to achieve the latter is innovative, because instead of eliminating these stromal cells which help the tumour, the objective has been their selective reprogramming. The researchers focused on a subpopulation of fibroblasts known to play a role in inflammation, because inflammation fosters tumour growth.

Their analysis revealed that the Saa3 gene is responsible for CAFs helping tumour cells to progress. When the researchers eliminated the expression of this gene in the CAFs, these cells behaved like normal fibroblasts, losing the ability to accelerate tumour cell progression. Researchers had managed to "reprogramme" these cells, which had been stripped of their pro-tumour properties.

In human samples of pancreatic cancer, the researchers have identified the same population of pro- tumour fibroblasts, and have observed that when the SAA1 gene (the human version of Saa3) is overexpressed, the prognosis for the patients is far worse.
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How to turn scar tissue into healthy tissue

Limited therapeutic options and the heart's inability to regenerate healthy cells after heart attacks are parts of factors that cause sudden death in heart attack patients. Scientists are exploring ways to reprogram scar tissue cells into healthy heart muscle cells to reduce death.

Creation of cardiomyocytes with genetic signatures that closely mimic those found in healthy adult heart muscle cells can solve the problem. The other reprogramming approach leads to the creation of cardiomyocytes with more embryonic cell signatures.

The differences in the cardiomyocytes generated using these two methods are
Cardiomyocytes, the cells responsible for the beating of the heart, are essential to repairing the heart after injury. But after injury, such as a heart attack, many of these cells are irreversibly lost; they've been turned into scar tissue cells.

The replacement of these lost cells with patient-specific cardiomyocytes has gained attention as a potential therapy because existing healthy heart tissue better accepts these cells and because of increased recovery rates. Patient-specific cardiomyocytes also offer unique advantages for drug screens to help doctors identify each patient's drug type and dosage.

There are presently two widely practiced approaches to generate patient-specific cardiomyocytes.
In the first approach, an adult connective cell called a fibroblast is reprogrammed back into a naïve embryonic stem cell-like state. Once in this naïve state, the cell has the potential to develop into any cell type in the body, but scientists direct it to develop into a cardiomyocyte. These newly created cardiomyocytes are called induced pluripotent stem cell cardiomyocytes iPSC-CM.

In the second approach called direct cardiac reprogramming, a fibroblast is directly converted into a cardiomyocyte, without having to first be reprogrammed into a naïve embryonic stem cell. These new cardiomyocytes are called induced cardiomyocytes iCM. The researchers found that both methods resulted in cells with classic cardiomyocyte molecular features. However, by comparing the unique set of genes activated or not activated in each group of cells, the researchers found that iPSC-CMs more closely resembled embryonic cardiomyocytes, while iCMs more closely resembled adult cardiomyocytes.

Researchers also found that iPSC-CMs feature more active genes and a higher number of genes poised to be either activated or repressed a trait more commonly found in potent cells.
Metabolically, iPSC-CMs had a higher expression of glycolytic genes while iCMs had a higher expression of genes involved in fatty acid oxidation, the primary means of energy production in adult hearts.

In iPSC-CMs, heart muscle cells called sarcomeres, which give the heart a striated look, were less organized than in iCMs. The contractibility of cardiomyocytes as measured by the intake and removal of calcium was also greater in iCMs, suggesting that iCM cells are more mature than iPSC-CM cells.
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HIV reservoir marker makes it possible to kill the virus

Discovery of HIV marker makes it possible to differentiate between dominant HIV infected cells and healthy cells.

Researchers have discovered a way of isolating and analyzing reservoir cells that are responsible for hosting HIV virus.

HIV virus can hide in these reservoir cells for a long period of time, taking antiviral drugs does not stop the activities of the virus.

The discovery will make it possible to study viral reservoirs and therapeutic plan to kill the hidden HIV virus.