Even in the worst COVID-19 cases, the body launches immune cells to fight back
International collaboration provides important piece of COVID-19 puzzle
June 29, 2020
Science Daily/La Jolla Institute for Immunology
A new study from researchers at La Jolla Institute for Immunology (LJI) and Erasmus University Medical Center (Erasmus MC) shows that even the sickest COVID-19 patients produce T cells that help fight the virus. The study offers further evidence that a COVID-19 vaccine will need to elicit T cells to work alongside antibodies.
The research, published June 26, 2020 in Science Immunology, also reveals that both Dutch and American patients have similar responses to the virus. "This is key to understanding how the immune response fights the virus," says LJI Professor Alessandro Sette, Dr. Biol. Sci., who co-led the study with Erasmus MC Virologist Rory de Vries, Ph.D. "You want vaccine approaches to be grounded in observations from rather diverse settings to ensure that the results are generally applicable."
For the study, the researchers followed ten COVID-19 patients with the most severe disease symptoms. All ten were admitted to the ICU at Erasmus University Medical Center, in the Netherlands, and put on ventilators as part of their care. Two of the patients eventually died of the disease. An in-depth look at their immune system responses showed that all ten patients produced T cells that targeted the SARS-CoV-2 virus. These T cells worked alongside antibodies to try to clear the virus and stop the infection.
"Activating these cells appears to be at least as important as the production of antibodies," says Erasmus MC Virologist Rory de Vries, Ph.D., who co-led the study with Sette.
These findings are in line with a recent Cell study from Sette, LJI Professor Shane Crotty, Ph.D., and LJI colleagues that showed a robust T cell response in individuals with moderate cases of COVID-19. In both studies, the T cells in these patients prominently targeted the "spike" protein on SARS-CoV-2. The virus uses the spike protein to enter host cells, and many vaccine efforts around the world are aimed at getting the immune system to recognize and attack this protein. The new study offers further evidence that the spike protein is a promising target and confirms that the immune system can also mount strong responses to other targets on the virus.
"This is good news for those making a vaccine using spike, and it also suggests new avenues to potentially increase vaccine potency," says Daniela Weiskopf, Ph.D., research assistant professor at LJI and first author of the new study.
The collaboration between scientists in La Jolla and the Netherlands is also a part of a larger picture, and emphasizes the highly collaborative philosophy adopted by the LJI group. Sette is a world leader in understanding what specific pieces (or epitopes) the immune system recognizes when it encounters a new microbe. The Sette lab's work in defining epitope sets to allow to measure SARS-CoV-2 T cell responses was a key element of the study.
In fact, LJI has become a hub for COVID-19 T cell studies, and Sette has sent out reagents to more than 60 labs around the world. "The study is also highly significant because it illustrates how science has no frontiers," says Sette. "To truly understand a global pandemic, our approach needs to be global, and we need to study effective immune response in people with different genetic backgrounds, living in different environments."
While the Cell paper followed San Diego residents, the new paper follows Dutch patients -- and the T cell responses were consistent in both populations. "This study is important because it shows this immune response in patients thousands of miles apart," says Weiskopf. "The same observation has now been strongly reproduced in different continents and different studies."
https://www.sciencedaily.com/releases/2020/06/200629124106.htm
The harmful effects of stress during pregnancy can last a lifetime
March 5, 2020
Science Daily/Yale University
Mice exposed to stress in the womb and soon after birth can expect a lifetime of immune system deficiencies that hinder the ability to ward off infections and cancer, Yale University researchers report March 5 in the journal Cell.
In a new study, they tracked a lifetime of physiological changes experienced by mice given a liquid solution containing the stress hormone glucocorticoid while in the womb or soon after birth. Glucocorticoids are naturally occurring hormones that reduce inflammation and are instrumental in helping infants and adults alike adapt quickly to environmental dangers, such as famine or violence. Physicians use them to treat asthma and autoimmune diseases caused by overactive immune systems, for example.
But, the researchers found, early-life exposure to the stress hormone can permanently alter many immune system responses, decreasing the body's ability to ward off bacterial infections and fight tumors.
"Mice for rest of their lives are rewired and reprogrammed in ways fundamentally different from those not exposed to glucocorticoids," said Yale immunobiologist Ruslan Medzhitov, senior author of the study and Howard Hughes Medical Institute investigator.
Medzhitov and first author Jun Young Hun, also of Yale, catalogued a host of physiological changes that occurred in mice given glucocorticoids and that had serious consequences for the rest of their lives. As adults, for instance, the exposed mice were more susceptible to bacterial infections and tumors than mice without exposure. One specific physiological change was decreased activity in a key T cell that responds to pathogens and other threats to the host.
The study helps explain why individuals vary so widely in their ability to ward off infections, the authors said. It also provides an explanation for a social phenomenon found throughout human history: an emphasis on shielding women from stress during pregnancy.
"In all cultures, there are efforts to shelter women from stress during pregnancy," he said. "The effects of early life stress don't just go away."
As more is learned about molecular changes caused by early exposure to stress, the more likely it is that medical science will find a way to minimize its damage, said the authors.
"We aren't there yet," Medzhitov said.
https://www.sciencedaily.com/releases/2020/03/200305132154.htm
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Hookworm trial offers new hope to MS patients
June 18, 2020
Science Daily/University of Nottingham
Parasitic worms could offer a new treatment hope for patients suffering from the autoimmune disease multiple sclerosis, according to experts from the University of Nottingham.
The findings of the research, published in the journal JAMA Neurology, show that infecting MS patients with a safe dose of the hookworm parasite Necator americanus induces immunoregulatory responses and boosts the number of cells which help keep the immune system under control.
The research was led by Cris Constantinescu, Professor of Neurology in the University's School of Clinical Sciences and a leading MS expert, and David Idris Pritchard, Professor of Parasite Immunology in the University's School of Pharmacy, who has spent decades studying the biology of the hookworm. The study was funded by the Multiple Sclerosis Society.
MS is a condition that can affect the brain and spinal cord, causing a wide range of potential symptoms, including problems with vision, arm or leg movement, sensation or balance. Whilst treatments are available, there is currently no cure.
The study aimed to show that the presence of hookworms in the body switches off the mechanism by which the body's immune system becomes overactive -- the main cause of MS -- reducing both the severity of symptoms and the number of relapses experienced by the patients.
71 patients were recruited for a controlled clinical trial who suffer from the most common type of the disease, relapsing remitting MS (RRMS).
Symptoms in patients such as vision problems, dizziness and fatigue, appear and then fade away either partially or completely, and secondary progressive MS with superimposed relapses.
Half of the patients on the trial, received a low dose of the hookworms -- 25 of the microscopic larvae -- on a plaster applied to the arm, while the other half received a placebo plaster.
At the beginning of the trial, the participants underwent an MRI scan to record the scarring or lesions on the brain which are present in MS patients. Over the course of nine months, all the patients were scanned on a regular basis for new or worsening lesions which can be a tell-tale sign of relapse.
The results at the end of the trial showed that the total number of new MRI lesions did not differ significantly between patients receiving hookworm and those receiving placebo. However, more than half the patients on hookworm had no new lesions at all.
In addition, the scientists found an increase in the percentage of regulatory T cells found within patients who received the hookworm. These cells help to keep the immune system under control, and are deficient in MS patients. The results showed that the hookworm increases this type of cell which could be beneficial in the treatment of MS.
Professor Constantinescu said: "The findings of our study are encouraging. Whilst the results are modest in comparison to the current very potent and highly effective treatments available, some patients with milder disease or more inclined for natural treatments may consider this as an option.
"On the more biological level, it is worth harnessing immunoregulatory mechanisms, for example increasing regulatory T cells in MS (and possibly other autoimmune diseases). Further studies are now needed to establish whether different protocols can enhance this benefit. For instance, would a booster infection in around nine months enhance the regulatory T cells responses and enhance the clinical/radiological benefit?"
Professor Pritchard is equally encouraged by the results of the trial. He said: "In essence, we were able to safely and easily deliver a living drug to humans, an organism which has long lasting modulatory effects on the immune system, given the time the adult parasite is resident in the small intestine (years). Clearly, this study has set the scene for follow up trials, where I would envisage booster infections being given to enhance the immune modulation already recorded. The dosage used in the current study (25 larvae) was the maximum permitted under regulatory guidelines, therefore boosting with this dose would be preferable to increasing the level of primary exposure."
https://www.sciencedaily.com/releases/2020/06/200618150223.htm
How sleep can fight infection
February 12, 2019
Science Daily/Rockefeller University Press
Researchers have discovered why sleep can sometimes be the best medicine. Sleep improves the potential ability of some of the body's immune cells to attach to their targets, according to a new study. The study helps explain how sleep can fight off an infection, whereas other conditions, such as chronic stress, can make the body more susceptible to illness.
T cells are a type of white blood cell that are critical to the body's immune response. When T cells recognize a specific target, such as a cell infected with a virus, they activate sticky proteins known as integrins that allow them to attach to their target and, in the case of a virally infected cell, kill it. While much is known about the signals that activate integrins, signals that might dampen the ability of T cells to attach to their targets are less well understood.
Stoyan Dimitrov and colleagues at the University of Tübingen decided to investigate the effects of a diverse group of signaling molecules known as G?s-coupled receptor agonists. Many of these molecules can suppress the immune system, but whether they inhibit the ability of T cells to activate their integrins and attach to target cells was unknown.
Dimitrov and colleagues found that certain G?s-coupled receptor agonists, including the hormones adrenaline and noradrenaline, the proinflammatory molecules prostaglandin E2 and D2, and the neuromodulator adenosine, prevented T cells from activating their integrins after recognizing their target. "The levels of these molecules needed to inhibit integrin activation are observed in many pathological conditions, such as tumor growth, malaria infection, hypoxia, and stress," says Dimitrov. "This pathway may therefore contribute to the immune suppression associated with these pathologies."
Adrenaline and prostaglandin levels dip while the body is asleep. Dimitrov and colleagues compared T cells taken from healthy volunteers while they slept or stayed awake all night. T cells taken from sleeping volunteers showed significantly higher levels of integrin activation than T cells taken from wakeful subjects. The researchers were able to confirm that the beneficial effect of sleep on T cell integrin activation was due to the decrease in G?s-coupled receptor activation.
"Our findings show that sleep has the potential to enhance the efficiency of T cell responses, which is especially relevant in light of the high prevalence of sleep disorders and conditions characterized by impaired sleep, such as depression, chronic stress, aging, and shift work," says last author Luciana Besedovsky.
In addition to helping explain the beneficial effects of sleep and the negative effects of conditions such as stress, Dimitrov and colleagues' study could spur the development of new therapeutic strategies that improve the ability of T cells to attach to their targets. This could be useful, for example, for cancer immunotherapy, where T cells are prompted to attack and kill tumor cells.
https://www.sciencedaily.com/releases/2019/02/190212094839.htm