Vitamin D levels appear to play role in COVID-19 mortality rates

Vitamin D levels appear to play role in COVID-19 mortality rates

After studying global data from the novel coronavirus (COVID-19) pandemic, researchers have discovered a strong correlation between severe vitamin D deficiency and mortality rates.

Led by Northwestern University, the research team conducted a statistical analysis of data from hospitals and clinics across China, France, Germany, Italy, Iran, South Korea, Spain, Switzerland, the United Kingdom (UK) and the United States.

The researchers noted that patients from countries with high COVID-19 mortality rates, such as Italy, Spain and the UK, had lower levels of vitamin D compared to patients in countries that were not as severely affected.

This does not mean that everyone -- especially those without a known deficiency -- needs to start hoarding supplements, the researchers caution.

"While I think it is important for people to know that vitamin D deficiency might play a role in mortality, we don't need to push vitamin D on everybody," said Northwestern's Vadim Backman, who led the research. "This needs further study, and I hope our work will stimulate interest in this area. The data also may illuminate the mechanism of mortality, which, if proven, could lead to new therapeutic targets."

The research is available on medRxiv, a preprint server for health sciences.

Backman is the Walter Dill Scott Professor of Biomedical Engineering at Northwestern's McCormick School of Engineering. Ali Daneshkhah, a postdoctoral research associate in Backman's laboratory, is the paper's first author.

Backman and his team were inspired to examine vitamin D levels after noticing unexplained differences in COVID-19 mortality rates from country to country. Some people hypothesized that differences in healthcare quality, age distributions in population, testing rates or different strains of the coronavirus might be responsible. But Backman remained skeptical.

"None of these factors appears to play a significant role," Backman said. "The healthcare system in northern Italy is one of the best in the world. Differences in mortality exist even if one looks across the same age group. And, while the restrictions on testing do indeed vary, the disparities in mortality still exist even when we looked at countries or populations for which similar testing rates apply.

"Instead, we saw a significant correlation with vitamin D deficiency," he said.

By analyzing publicly available patient data from around the globe, Backman and his team discovered a strong correlation between vitamin D levels and cytokine storm -- a hyperinflammatory condition caused by an overactive immune system -- as well as a correlation between vitamin D deficiency and mortality.

"Cytokine storm can severely damage lungs and lead to acute respiratory distress syndrome and death in patients," Daneshkhah said. "This is what seems to kill a majority of COVID-19 patients, not the destruction of the lungs by the virus itself. It is the complications from the misdirected fire from the immune system."

This is exactly where Backman believes vitamin D plays a major role. Not only does vitamin D enhance our innate immune systems, it also prevents our immune systems from becoming dangerously overactive. This means that having healthy levels of vitamin D could protect patients against severe complications, including death, from COVID-19.

"Our analysis shows that it might be as high as cutting the mortality rate in half," Backman said. "It will not prevent a patient from contracting the virus, but it may reduce complications and prevent death in those who are infected."

Backman said this correlation might help explain the many mysteries surrounding COVID-19, such as why children are less likely to die. Children do not yet have a fully developed acquired immune system, which is the immune system's second line of defense and more likely to overreact.

"Children primarily rely on their innate immune system," Backman said. "This may explain why their mortality rate is lower."

Backman is careful to note that people should not take excessive doses of vitamin D, which might come with negative side effects. He said the subject needs much more research to know how vitamin D could be used most effectively to protect against COVID-19 complications.

"It is hard to say which dose is most beneficial for COVID-19," Backman said. "However, it is clear that vitamin D deficiency is harmful, and it can be easily addressed with appropriate supplementation. This might be another key to helping protect vulnerable populations, such as African-American and elderly patients, who have a prevalence of vitamin D deficiency."

Backman is the director of Northwestern's Center for Physical Genomics and Engineering and the associate director for Research Technology and Infrastructure at the Robert H. Lurie Comprehensive Cancer Center at Northwestern University.

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Story Source:

Materials provided by Northwestern University. Original written by Amanda Morris. Note: Content may be edited for style and length.

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Journal Reference:

1. Ali Daneshkhah, Vasundhara Agrawal, Adam Eshein, Hariharan Subramanian, Hemant Kumar Roy, Vadim Backman. The Possible Role of Vitamin D in Suppressing Cytokine Storm and Associated Mortality in COVID-19 Patients. medRxiv, Posted April 30, 2020; [link]

Vitamin D levels appear to play role in COVID-19 mortality rates

Doctor, vitamin D concept (stock image).

After studying global data from the novel coronavirus (COVID-19) pandemic, researchers have discovered a strong correlation between severe vitamin D deficiency and mortality rates.

Led by Northwestern University, the research team conducted a statistical analysis of data from hospitals and clinics across China, France, Germany, Italy, Iran, South Korea, Spain, Switzerland, the United Kingdom (UK) and the United States.

The researchers noted that patients from countries with high COVID-19 mortality rates, such as Italy, Spain and the UK, had lower levels of vitamin D compared to patients in countries that were not as severely affected.

This does not mean that everyone -- especially those without a known deficiency -- needs to start hoarding supplements, the researchers caution.

"While I think it is important for people to know that vitamin D deficiency might play a role in mortality, we don't need to push vitamin D on everybody," said Northwestern's Vadim Backman, who led the research. "This needs further study, and I hope our work will stimulate interest in this area. The data also may illuminate the mechanism of mortality, which, if proven, could lead to new therapeutic targets."

The research is available on medRxiv, a preprint server for health sciences.

Backman is the Walter Dill Scott Professor of Biomedical Engineering at Northwestern's McCormick School of Engineering. Ali Daneshkhah, a postdoctoral research associate in Backman's laboratory, is the paper's first author.

Backman and his team were inspired to examine vitamin D levels after noticing unexplained differences in COVID-19 mortality rates from country to country. Some people hypothesized that differences in healthcare quality, age distributions in population, testing rates or different strains of the coronavirus might be responsible. But Backman remained skeptical.

"None of these factors appears to play a significant role," Backman said. "The healthcare system in northern Italy is one of the best in the world. Differences in mortality exist even if one looks across the same age group. And, while the restrictions on testing do indeed vary, the disparities in mortality still exist even when we looked at countries or populations for which similar testing rates apply.

"Instead, we saw a significant correlation with vitamin D deficiency," he said.

By analyzing publicly available patient data from around the globe, Backman and his team discovered a strong correlation between vitamin D levels and cytokine storm -- a hyperinflammatory condition caused by an overactive immune system -- as well as a correlation between vitamin D deficiency and mortality.

"Cytokine storm can severely damage lungs and lead to acute respiratory distress syndrome and death in patients," Daneshkhah said. "This is what seems to kill a majority of COVID-19 patients, not the destruction of the lungs by the virus itself. It is the complications from the misdirected fire from the immune system."

This is exactly where Backman believes vitamin D plays a major role. Not only does vitamin D enhance our innate immune systems, it also prevents our immune systems from becoming dangerously overactive. This means that having healthy levels of vitamin D could protect patients against severe complications, including death, from COVID-19.

"Our analysis shows that it might be as high as cutting the mortality rate in half," Backman said. "It will not prevent a patient from contracting the virus, but it may reduce complications and prevent death in those who are infected."

Backman said this correlation might help explain the many mysteries surrounding COVID-19, such as why children are less likely to die. Children do not yet have a fully developed acquired immune system, which is the immune system's second line of defense and more likely to overreact.

"Children primarily rely on their innate immune system," Backman said. "This may explain why their mortality rate is lower."

Backman is careful to note that people should not take excessive doses of vitamin D, which might come with negative side effects. He said the subject needs much more research to know how vitamin D could be used most effectively to protect against COVID-19 complications.

"It is hard to say which dose is most beneficial for COVID-19," Backman said. "However, it is clear that vitamin D deficiency is harmful, and it can be easily addressed with appropriate supplementation. This might be another key to helping protect vulnerable populations, such as African-American and elderly patients, who have a prevalence of vitamin D deficiency."

Backman is the director of Northwestern's Center for Physical Genomics and Engineering and the associate director for Research Technology and Infrastructure at the Robert H. Lurie Comprehensive Cancer Center at Northwestern University.

---

Story Source:

Materials provided by Northwestern University. Original written by Amanda Morris. Note: Content may be edited for style and length.

---

Journal Reference:

1. Ali Daneshkhah, Vasundhara Agrawal, Adam Eshein, Hariharan Subramanian, Hemant Kumar Roy, Vadim Backman. The Possible Role of Vitamin D in Suppressing Cytokine Storm and Associated Mortality in COVID-19 Patients. medRxiv, Posted April 30, 2020; [link]

Little-known protein appears to play important role in obesity and metabolic disease

Obese related protein structure

With unexpected findings about a protein that's highly expressed in fat tissue, scientists at Scripps Research have opened the door to critical new understandings about obesity and metabolism. Their discovery, which appears Nov. 20 in the journal Nature, could lead to new approaches for addressing obesity and potentially many other diseases.

The signaling protein, known as PGRMC2, had not been extensively studied in the past. Short for "progesterone receptor membrane component 2," it had been detected in the uterus, liver and several areas of the body. But the lab of Enrique Saez, PhD, saw that it was most abundant in fat tissue -- particularly in brown fat, which turns food into heat to maintain body temperature -- and became interested in its function there.

An important role: heme's travel guide

The team built on their recent discovery that PGRMC2 binds to and releases an essential molecule called heme. Recently in the spotlight for its role in providing flavor to the plant-based Impossible Burger, heme holds a much more significant role in the body. The iron-containing molecule travels within cells to enable crucial life processes such as cellular respiration, cell proliferation, cell death and circadian rhythms.

Using biochemical techniques and advanced assays in cells, Saez and his team found that PGRMC2 is a "chaperone" of heme, encapsulating the molecule and transporting it from the cell's mitochondria, where heme is created, to the nucleus, where it helps carry out important functions. Without a protective chaperone, heme would react with -- and destroy -- everything in its path.

"Heme's significance to many cellular processes has been known for a long time," says Saez, associate professor in the Department of Molecular Medicine. "But we also knew that heme is toxic to the cellular materials around it and would need some sort of shuttling pathway. Until now, there were many hypotheses, but the proteins that traffic heme had not been identified."

An innovative approach for obesity?

Through studies involving mice, the scientists established PGRMC2 as the first intracellular heme chaperone to be described in mammals. However, they didn't stop there; they sought to find out what happens in the body if this protein doesn't exist to transport heme.

And that's how they made their next big discovery: Without PGRMC2 present in their fat tissues, mice that were fed a high-fat diet became intolerant to glucose and insensitive to insulin -- hallmark symptoms of diabetes and other metabolic diseases. By contrast, obese-diabetic mice that were treated with a drug to activate PGRMC2 function showed a substantial improvement of symptoms associated with diabetes.

"We saw the mice get better, becoming more glucose tolerant and less resistant to insulin," Saez says. "Our findings suggest that modulating PGRMC2 activity in fat tissue may be a useful pharmacological approach for reverting some of the serious health effects of obesity."

The team also evaluated how the protein changes other functions of brown and white fat, says the study's lead author, Andrea Galmozzi, PhD. "The first surprise finding was that the brown fat looked white," he says.

Brown fat, which is normally the highest in heme content, is often considered the "good fat." One of its key roles is to generate heat to maintain body temperature. Among mice that were unable to produce PGRMC2 in their fat tissues, temperatures dropped quickly when placed in a cold environment.

"Even though their brain was sending the right signals to turn on the heat, the mice were unable to defend their body temperature," Galmozzi says. "Without heme, you get mitochondrial dysfunction and the cell has no means to burn energy to generate heat."

Saez believes it's possible that activating the heme chaperone in other organs -- including the liver, where a large amount of heme is made -- could help mitigate the effects of other metabolic disorders such as non-alcoholic steatohepatitis (NASH), which is a major cause of liver transplantation today.

"We're curious to know whether this protein performs the same role in other tissues where we see defects in heme that result in disease" Saez says.

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Story Source:

Materials provided by Scripps Research Institute. Note: Content may be edited for style and length.

Not so selfish after all -- Key role of transposable elements in mammalian evolution

The human genome contains 4.5 million copies of transposable elements (TEs), so-called selfish DNA sequences capable of moving around the genome through cut-and-paste or copy-and-paste mechanisms. Accounting for 30-50% of all of the DNA in the average mammalian genome, these TEs have conventionally been viewed as genetic freeloaders, hitchhiking along in the genome without providing any benefit to the host organism. More recently, however, scientists have begun to uncover cases in which TE sequences have been co-opted by the host to provide a useful function, such as encoding part of a host protein. In a new study published in the journal Nucleic Acids Research, Professor Hidenori Nishihara has undertaken one of the most comprehensive analyses of TE sequence co-option to date, uncovering tens of thousands of potentially co-opted TE sequences and suggesting that they have played a key role in mammalian evolution.

"I was specifically interested in the potential influence of TE sequences on the evolution of the mammary gland," notes Dr. Nishihara, "an organ that is responsible for producing milk and is, as the name suggests, a key distinguishing feature of mammals." To identify potentially co-opted TE sequences, Dr. Nishihara used four proteins -- ER?, FoxA1, GATA3, and AP2? -- that bind to DNA to regulate the production of proteins involved in mammary gland development. Dr. Nishihara then located all of the DNA sequences in the genome to which these proteins bind. Surprisingly, 20-30% of all of the binding sites across the genome were located in TEs, with as many as 38,500 TEs containing at least one binding site. The majority of these were in a copy-and-paste type of TE known as a retrotransposon, which duplicates itself, leaving a new copy in a new location.

The TE-derived binding site sequences were more conserved across species than expected, indicating that they are being preserved by evolution because they serve some important function. Dr. Nishihara believes that these TE sequences have been co-opted to serve as enhancers, DNA elements that increase the transcription of nearby genes. By binding to one of the four master regulators of mammary gland development, these enhancers ultimately increase the production of proteins involved in mammary gland development.

Dr. Nishihara then investigated when in mammalian evolution these TE sequences were acquired and found two distinct phases of acquisition: roughly 60-70% were acquired in the ancestor of all placental mammals (Eutheria), while 10-20% could be traced back to the ancestor of New World monkeys (Simiiformes). In addition, there appeared to be another wave of acquisition of ER? binding sites in the ancestor of mice and rats (Muridae). Thus, by providing a vast number of potential regulatory element binding sites throughout the genome, TEs may have had a substantial impact on the emergence of the mammary gland and its evolution within mammals.

Dr. Nishihara's study sheds light on the deep involvement of TEs in the evolution of mammary gland regulatory elements. However, it remains unclear how common this mode of TE-mediated regulatory network evolution is. Dr. Nishihara, at least, believes that the mammary gland is not unique in this respect. He notes that, "in addition to mammary glands, mammals share many features, such as the neocortex, closed secondary palate, and hair. I expect future research to uncover many additional kinds of TEs that have been similarly involved in the evolution of these features in mammals."

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Story Source:

Materials provided by Tokyo Institute of Technology. Note: Content may be edited for style and length.

Probing the role of an inflammation resolution sensor in obesity and heart failure

After heart attack injury, several fatty-acid-derived bioactive molecules -- including one called resolvin D1 -- play an essential signaling role to safely clear inflammation and help repair heart muscle. The mechanism of how this resolution occurs is not well-understood.

There is a receptor on the surface of many immune cells called ALX/FRP2, and in models of atherosclerosis, ALX/FPR2 is known to act as a sensor to help resolve inflammation.

In a 2015 study using a mouse model, University of Alabama at Birmingham researcher Ganesh Halade, Ph.D., observed that, after heart attack injury, ALX/FPR2 was highly expressed in immune myeloid cells and was activated by resolvin D1 in immune cells in the spleen and in immune cells at the heart attack site. The result was an expedited resolution of the heart attack injury. Resolvin D1 is one of the omega 3 fatty-acid metabolites known as specialized pro-resolving mediators, or SPMs, that help clear inflammation.

Now, Halade and colleagues at UAB, Boston and France have used mice that completely lack ALX/FPR2 to learn more about the pathways this resolution sensor uses to target inflammation. Such knowledge will help in finding treatments to delay the human heart failure that often follows a heart attack.

Before beginning the mouse studies, Halade and colleagues examined heart muscle tissue from patients with heart failure. They found that ALX/FPR2 was plentiful in these human ischemic hearts, and it was located in the cytoplasm of the myocardium cells. In contrast, in healthy human heart tissue, ALX/FPR2 was limited to the cell membrane. To learn more, they then expanded study of the precise and comprehensive role of the resolution receptor using mice having an ALX/FPR2 gene deletion.

The researchers found that mice lacking ALX/FPR2 showed spontaneous, age-related obesity. With the obesity, the ALX/FPR2-null mice developed heart disease that weakened the heart's ability to pump blood, and they had a shortened lifespan with aging. The aging mice also developed kidney inflammation, as shown by increased inflammation markers like NGAL, TNF-alpha and CCL2, and elevated plasma creatinine levels.

After a heart attack in normal mice, leukocyte immune cells in the spleen produce SPMs. However, in the ALX/FPR2-null mice, the researchers found lower levels of SPMs in the heart and the spleen after heart attack, indicative of non-resolving inflammation. Halade says this suggested impaired cross-talk between the injured heart and splenic leukocytes, a cross-talk that is required for the resolution of inflammation. In addition to the lower levels of SPMs, the ALX/FPR2-null mice showed dysregulation of several immune responsive enzymes -- lower levels of LOX enzymes and increased levels of the pro-inflammatory COX-1 and COX-2 enzymes.

Finally, the ALX/FPR2-null mice showed impairment of activated macrophage cells to phagocytose -- that is, to "eat" infecting microbes or dead human cells, one of the macrophage's prime functions. After heart attack, the ALX/FPR2-null mice had increased numbers of neutrophils, the first phagocytic responders after heart injury, in both the spleen and the left ventricle of the heart. Also, there were reduced numbers of reparative macrophages in both the spleen and the heart.

Altogether, says Halade, an associate professor in the UAB Department of Medicine Division of Cardiovascular Disease, these findings demonstrate the integrative role of ALX/FPR2 as a primary target to manage cardiometabolic health, inflammation-resolution processes and cardiorenal syndrome in aging.

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Story Source:

Materials provided by University of Alabama at Birmingham. Note: Content may be edited for style and length.

Little-known protein appears to play important role in obesity and metabolic disease

With unexpected findings about a protein that's highly expressed in fat tissue, scientists at Scripps Research have opened the door to critical new understandings about obesity and metabolism. Their discovery, which appears Nov. 20 in the journal Nature, could lead to new approaches for addressing obesity and potentially many other diseases.

The signaling protein, known as PGRMC2, had not been extensively studied in the past. Short for "progesterone receptor membrane component 2," it had been detected in the uterus, liver and several areas of the body. But the lab of Enrique Saez, PhD, saw that it was most abundant in fat tissue -- particularly in brown fat, which turns food into heat to maintain body temperature -- and became interested in its function there.

An important role: heme's travel guide

The team built on their recent discovery that PGRMC2 binds to and releases an essential molecule called heme. Recently in the spotlight for its role in providing flavor to the plant-based Impossible Burger, heme holds a much more significant role in the body. The iron-containing molecule travels within cells to enable crucial life processes such as cellular respiration, cell proliferation, cell death and circadian rhythms.

Using biochemical techniques and advanced assays in cells, Saez and his team found that PGRMC2 is a "chaperone" of heme, encapsulating the molecule and transporting it from the cell's mitochondria, where heme is created, to the nucleus, where it helps carry out important functions. Without a protective chaperone, heme would react with -- and destroy -- everything in its path.

"Heme's significance to many cellular processes has been known for a long time," says Saez, associate professor in the Department of Molecular Medicine. "But we also knew that heme is toxic to the cellular materials around it and would need some sort of shuttling pathway. Until now, there were many hypotheses, but the proteins that traffic heme had not been identified."

An innovative approach for obesity?

Through studies involving mice, the scientists established PGRMC2 as the first intracellular heme chaperone to be described in mammals. However, they didn't stop there; they sought to find out what happens in the body if this protein doesn't exist to transport heme.

And that's how they made their next big discovery: Without PGRMC2 present in their fat tissues, mice that were fed a high-fat diet became intolerant to glucose and insensitive to insulin -- hallmark symptoms of diabetes and other metabolic diseases. By contrast, obese-diabetic mice that were treated with a drug to activate PGRMC2 function showed a substantial improvement of symptoms associated with diabetes.

"We saw the mice get better, becoming more glucose tolerant and less resistant to insulin," Saez says. "Our findings suggest that modulating PGRMC2 activity in fat tissue may be a useful pharmacological approach for reverting some of the serious health effects of obesity."

The team also evaluated how the protein changes other functions of brown and white fat, says the study's lead author, Andrea Galmozzi, PhD. "The first surprise finding was that the brown fat looked white," he says.

Brown fat, which is normally the highest in heme content, is often considered the "good fat." One of its key roles is to generate heat to maintain body temperature. Among mice that were unable to produce PGRMC2 in their fat tissues, temperatures dropped quickly when placed in a cold environment.

"Even though their brain was sending the right signals to turn on the heat, the mice were unable to defend their body temperature," Galmozzi says. "Without heme, you get mitochondrial dysfunction and the cell has no means to burn energy to generate heat."

Saez believes it's possible that activating the heme chaperone in other organs -- including the liver, where a large amount of heme is made -- could help mitigate the effects of other metabolic disorders such as non-alcoholic steatohepatitis (NASH), which is a major cause of liver transplantation today.

"We're curious to know whether this protein performs the same role in other tissues where we see defects in heme that result in disease" Saez says.

---

Story Source:

Materials provided by Scripps Research Institute. Note: Content may be edited for style and length.