While most people infected with the SARS-CoV-2 virus experience relatively mild symptoms, some patients mount an aberrant inflammatory response that can damage the lungs and cause acute respiratory distress syndrome (ARDS), potentially resulting in the patient's death. However, the immune cells and inflammatory molecules responsible for ARDS associated with COVID-19 remain unclear.

Unconventional T cells are a diverse class of immune cells that help control the response to viral infection and are commonly found in the lungs and other mucosal tissues in the body. "Despite this, the role of unconventional T cells in the pathophysiological process of SARS-CoV-2-driven ARDS has not yet been explored," says Christophe Paget, a researcher at the INSERM Research Center for Respiratory Diseases, University of Tours.

Paget and colleagues, including co-lead author Youenn Jouan, an intensivist at the academic hospital of Tours, examined 30 patients admitted to intensive care with severe COVID-19 and compared the immune cells in their blood and lungs to those found in healthy volunteers or patients admitted to the ICU for reasons other than COVID-19.

The researchers found that two types of unconventional T cells -- known as mucosal-associated invariant T (MAIT) and invariant natural killer T (iNKT) cells -- were dramatically reduced in the blood of patients with severe COVID-19. However, the number of MAIT cells increased in the patients' airways, suggesting that these cells might move from the blood to the lungs to control the response to SARS-CoV-2 infection.

The MAIT and iNKT cells of COVID-19 patients appeared to be highly activated and produced distinct sets of inflammatory molecules. The researchers found that patients whose circulating MAIT and iNKT cells were particularly active at the time of their admittance to the ICU were less susceptible to hypoxemia (low blood oxygen levels) and were discharged sooner than patients whose MAIT and iNKT cells were less active.

"This suggests that MAIT and iNKT cells might play a beneficial role during severe COVID-19, although their precise functions and associated mechanisms require further investigation," says Jouan.

"Altogether, our findings should encourage further studies on MAIT and iNKT cells in SARS-CoV-2-induced ARDS to assess their potential as biomarkers and/or targets for immune intervention strategies," adds Paget.

In a study appearing online Aug. 24 in the journal Nature Communications, a research team led by the Duke Cancer Institute has identified the mechanisms at work, describing how breast cancer cells use cholesterol to develop tolerance to stress, making them impervious to death as they migrate from the original tumor site.

"Most cancer cells die as they try to metastasize -- it's a very stressful process," said senior author Donald P. McDonnell, Ph.D., professor in the departments of Pharmacology and Cancer Biology and Medicine at Duke University School of Medicine. "The few that don't die have this ability to overcome the cell's stress-induced death mechanism. We found that cholesterol was integral in fueling this ability."

McDonnell and colleagues built on earlier research in their lab focusing on the link between high cholesterol and estrogen-positive breast and gynecological cancers. Those studies found that cancers fueled by the estrogen hormone benefitted from derivatives of cholesterol that act like estrogen, stoking cancer growth.

But a paradox emerged for estrogen-negative breast cancers. These cancers are not dependent on estrogens, but high cholesterol is still associated with worse disease, suggesting a different mechanism might be at work.

In the current study using cancer cell lines and mouse models, the Duke researchers found that migrating cancer cells gobble cholesterol in response to stress. Most die.

But in the what-doesn't-kill-you-makes-you-stronger motif, those that live emerge with a super-power that makes them able to withstand ferroptosis, a natural process in which cells succumb to stress. These stress-impervious cancer cells then proliferate and readily metastasize.

The process appears to be used not only by ER-negative breast cancer cells, but other types of tumors, including melanoma. And the mechanisms identified could be targeted by therapies.

"Unraveling this pathway has highlighted new approaches that may be useful for the treatment of advanced disease," McDonnell said. "There are contemporary therapies under development that inhibit the pathway we've described. Importantly, these findings yet again highlight why lowering cholesterol -- either using drugs or by dietary modification -- is a good idea for better health."

In addition to McDonnell, study authors include Wen Liu, Rachid Safi, Dmitri Kazmi, Binita Chakraborty and Ching-yi Chang.

The study received funding support from The Department of Defense Breast Cancer Research Program and the National Institutes of Health.

Source:https://www.sciencedaily.com/releases/2021/08/210824083507.htm 

"Despite the very high prevalence of iron deficiency in pregnancy, and how easy it is to treat, we are not doing a very good job of checking for it," said lead study author Jennifer Teichman, MD, of the University of Toronto, Canada and its affiliated hospitals including St. Michael's Hospital/Unity Health Toronto, where the study was conducted. "It's not top of mind, in part, because of inconsistent recommendations for ferritin testing across clinical guidelines."

Iron requirements in pregnancy are high to support the developing fetus, the growing placenta, and the increased blood supply needed to sustain the pregnancy. This demand for iron increases over the course of pregnancy. Iron deficiency is the most common cause of anemia (low hemoglobin or red blood cell count) during pregnancy, which has been linked to poorer outcomes for both mother and baby, including a higher risk of premature delivery, low birth weight, post-partum depression, and even maternal death. Anemia early in pregnancy has also been associated with neurodevelopmental delays in the offspring, even as the child approaches school age and beyond, which points to potentially long-lasting effects. Even low levels of iron alone can cause pregnant women to experience fatigue, weakness, and brain fog, Dr. Teichman explained.

The study included 44,552 pregnant women who received prenatal testing at community laboratories in Ontario, Canada, between 2013 and 2018 to determine how often ferritin testing was offered. Researchers also sought to provide more robust data about the prevalence and severity of iron deficiency among pregnant women and to identify whether certain clinical or demographic factors played a role in the likelihood of someone receiving a ferritin test.

Altogether, about 60% of patients got a ferritin test during pregnancy; 40% did not. Most tests were ordered by general practitioners (48%) and obstetricians/gynecologists (32%). The vast majority of ferritin testing (71%) occurred at or around the time of the first prenatal visit, when the risk of iron deficiency is lowest and, often, patients' iron levels were only checked once during their pregnancy.

"Iron deficiency becomes more common as women progress through pregnancy," said Dr. Teichman. "If we don't re-evaluate iron stores later in pregnancy, we miss a lot of women who are becoming iron deficient in later trimesters."

Dr. Teichman emphasized that the women in the study received care in Canada, a publicly funded health care system, which means patients don't incur the cost of ferritin testing. Despite this, the researchers found that women of lower socioeconomic status were less likely to be tested for iron deficiency, which further underscores differences in access to care and how clinicians may treat these patients differently.

Based on their findings, Dr. Teichman urges pregnant women -- and those who plan to become pregnant -- to ask about their iron levels before and during their pregnancy.

"Iron deficiency is very common, and there can be poor outcomes for both mom and baby if it isn't identified and treated," she said. "The good news is that it's easily found with a simple blood test and completely correctable with iron supplements."

She is quick to caution that standard prenatal vitamins by themselves cannot treat iron deficiency.

"Prenatal vitamins contain only a sprinkling of iron and many combine iron with calcium, which can inhibit the absorption of iron," said Dr. Teichman. "The way to address the problem is by identifying iron deficiency early on and then supplementing women with therapeutic doses of iron, which has 10 times the amount found in most prenatal vitamins."

Another important step, she said, will be to revise guidelines to ensure women are screened appropriately. Currently, the United States Preventative Services Task Force does not recommend universal screening for iron deficiency in pregnancy, citing the evidence as "insufficient to assess the balance of benefits and harms of screening for iron deficiency anemia in pregnant women." But, as Dr. Teichman explained, there are now sufficient data showing the harms of iron deficiency and anemia in pregnancy, such that it would be unethical to conduct a study in which iron-deficient women are not given supplementation. Conversely, there are no conceivable harms to iron screening, she explained.

The study is limited to the Ontario region of Canada and didn't account for women who may have had a miscarriage, who received fragmented care, or were referred to a hospital-based obstetric practice. Information about patients' ethnicity and education levels were unavailable.

Source: https://www.sciencedaily.com/releases/2021/08/210830104917.htm 

"We know that there are a range of immune responses to COVID-19, and the biological processes underlying those responses are not well understood," said co-first author Jihoon Lee, a graduate student at Fred Hutchinson Cancer Research Center. "We analyzed thousands of biological markers linked to metabolic pathways that underlie the immune system and found some clues as to what immune-metabolic changes may be pivotal in severe disease. Our hope is that these observations of immune function will help others piece together the body's response to COVID-19. The deeper understanding gained here may eventually lead to better therapies that can more precisely target the most problematic immune or metabolic changes."

The researchers collected 374 blood samples -- two draws per patient during the first week after being diagnosed with SARS-CoV-2 infection -- and analyzed their plasma and single immune cells. The analysis included 1,387 genes involved in metabolic pathways and 1,050 plasma metabolites.

In plasma samples, the team found that increased COVID-19 severity is associated with metabolite alterations, suggesting increased immune-related activity. Furthermore, through single-cell sequencing, researchers found that each major immune cell type has a distinct metabolic signature.

"We have found metabolic reprogramming that is highly specific to individual immune cell classes (e.g. "killer" CD8+ T cells, "helper" CD4+ T cells, antibody-secreting B cells, etc.) and even cell subtypes, and the complex metabolic reprogramming of the immune system is associated with the plasma global metabolome and are predictive of disease severity and even patient death," said co-first and co-corresponding author Dr. Yapeng Su, a research scientist at Institute for Systems Biology. "Such deep and clinically relevant insights on sophisticated metabolic reprogramming within our heterogeneous immune systems are otherwise impossible to gain without advanced single-cell multi-omic analysis."

"This work provides significant insights for developing more effective treatments against COVID-19. It also represents a major technological hurdle," said Dr. Jim Heath, president and professor of ISB and co-corresponding author on the paper. "Many of the data sets that are collected from these patients tend to measure very different aspects of the disease, and are analyzed in isolation. Of course, one would like these different views to contribute to an overall picture of the patient. The approach described here allows for the sum of the different data sets to be much greater than the parts, and provides for a much richer interpretation of the disease."

The research was conducted by scientists from ISB, Fred Hutchinson Cancer Research Center, Stanford University, Swedish Medical Center St. John's Cancer Institute at Saint John's Health Center, the University of Washington, the Howard Hughes Medical Institute.

Funding for this project comes from Merck and the Biomedical Advanced Research and Development Authority (BARDA), the Wilke Family Foundation, the MJ Murdock Charitable Trust, the Swedish Medical Center Foundation, the Parker Institute for Cancer Immunotherapy, Gilead, Amazon Web Services, and the National Institutes of Health.

Source:https://www.sciencedaily.com/releases/2021/09/210906111320.htm