Tag Archives: #bloodcells

Long-term Changes to Blood Cells Triggered by Covid-19 Infection (Medicine)

Using real-time deformability cytometry, researchers from the Max Planck Center for Physics and Medicine and FAU were able to prove for the first time that a Covid-19 infection causes significant changes in the size and stiffness of red and white blood cells, sometimes lasting several months. These findings may help to explain why some patients still suffer symptoms long after first contracting the virus (long Covid).

Shortness of breath, fatigue and headaches: some patients are left battling long-term side-effects of a severe Covid-19 infection for six months or even longer. We still do not entirely understand post Covid-19 syndrome, often referred to as long Covid. It has become apparent that the illness often impairs blood circulation, and may lead to dangerous congestion of blood vessels, restricting the transport of oxygen in the bloodstream. Blood cells and their physical properties have a key role to play in each of these phenomena.

Grafik zur Behandlung von Blutproben, um die physikalischen Eigenschaften von Leukozyten und Erythrozyten zu messen
Treating blood samples in order to measure the physical properties of leukocytes
and erythrocytes (image: MPI for the Science of Light/Guck Division)

Bearing this in mind, a team of researchers led by Markéta Kubánková, Jochen Guck and Martin Kräter from the Max Planck Center for Physics and Medicine, the Max Planck Institute for the Science of Light (MPL), FAU and the German Centre for Immunotherapy has investigated the mechanical properties of red and white blood cells.

‘We were able to measure significant and long-lasting changes to cells, both during the acute phase of the infection, and thereafter,’ reports Professor Guck, Chair of Biological Optomechanics at FAU and currently managing director of MPL. He explains that this has consequences for how Covid-19 is diagnosed and treated. The researchers have now published their findings in the Biophysical Journal.

They used a method they designed themselves called real-time deformability cytometry, RT-DC, which was recently awarded the prestigious Medical Valley Award, to analyse the blood cells.

This method involves sending blood cells through a narrow channel. The leukocytes and erythrocytes are stretched during the process. A high-speed camera then photographs every single one of them through a microscope, and special software determines the type of cell, its size and how severely deformed it is.

Using this method, up to 1,000 blood cells can be investigated per second. The advantage of the method is that is quick and the cells do not need to be dyed in a tricky and time-consuming procedure.

It is hoped that the method may act in future as an early warning system to recognise unknown viruses with the potential of triggering another pandemic.

The biophysicists from Erlangen were able to investigate more than four million blood cells from 17 patients currently in the acute phase of a Covid-19 infection, 14 individuals who have recovered from an infection and 24 healthy individuals.

Their findings showed that the size and malleability of red blood cells varied considerably more in those suffering from the disease than in the healthy volunteers. This indicates that the disease damages blood cells and may explain the increased risk of blood vessel congestion and blood clots in the lung. It may also explain why oxygen supply is impaired in those who have contracted the virus, as this is one of the main tasks carried out by erythrocytes.

As for white blood cells, the researchers found out that lymphocytes (white blood cells involved in the immune response) in Covid-19 patients exhibited a considerable decrease in stiffness, which may be an indication of a strong immune response.

The researchers observed a similar situation with neutrophilic granulocytes, a further group of white blood cells responsible for the intrinsic immune response. These cells remained dramatically altered even seven months after the acute infection.

‘We suspect that the immune cells’ cytoskeleton, which is responsible for determining cell function, has changed,’ explains Markéta Kubánková, lead author of the research article. In her opinion, real-time deformability cytometry could potentially be used routinely for diagnosing Covid-19, and even act as an early warning system in the future for detecting as yet unknown viruses with the potential of triggering a new pandemic.

Featured image: Diluting a blood sample (image: MPI for the Science of Light)

Original publication

Markéta Kubánková, Bettina Hohberger, Jakob Hoffmanns, Julia Fürst, Martin Herrmann, Jochen Guck, Martin Kräter: Physical phenotype of blood cells is altered in COVID-19, Biophysical Journal, 2021, ISSN 0006-3495, doi.org/10.1016/j.bpj.2021.05.025.

Provided by FAU

CNIC Scientists Identify Mutations Acquired by Blood Cells That Accelerate Heart Failure Progression (Medicine)

The study, carried out at the Centro Nacional de Investigaciones Cardiovasculares (CNIC) and the Hospital Universitario Virgen de Arrixaca in Murcia, establishes clonal hematopoiesis as a new cardiovascular risk factor and an important link between aging and cardiovascular disease

The adult human body produces hundreds of billions of blood cells every day. This essential process unavoidably leads to the appearance of mutations in the DNA of the progenitor cells. These are known as somatic mutations because they are acquired, not inherited. While most of these mutations are innocuous, occasionally a mutation gives affected cells a competitive advantage that allows them to expand progressively, generating clonal populations of blood cells. This phenomenon is known as clonal hematopoiesis

Now, a team of scientists at the Centro Nacional de Investigaciones Cardiovasculares (CNIC) and the Hospital Universitario Virgen de Arrixaca in Murcia has discovered that the presence of these acquired mutations in blood cells increases the risk of rapidly progressing heart failure, one of the chief causes of death in the world.

Clonal hematopoiesis is linked to aging, because over time there is an increasing chance that a culprit mutation will be produced, explained Dr. José Javier Fuster, coordinator of the study published today inThe Journal of the American College of Cardiology (JACC).

“Recent studies showed that people with clonal hematopoiesis have a higher risk of developing hematological cancers and dying. Curiously, however, the death of these patients is often due not to the cancer, but to cardiovascular causes.”

This new discovery has stimulated great interest in the possibility that clonal hematopoiesis might contribute to the increase in cardiovascular risk associated with aging.

Heart failure is the main cause of hospitalization among people older than 65 years and is a major cause of morbidity and mortality.

“There is established evidence linking clonal hematopoiesis to an increased risk of atherosclerosis, the underlying cause of most heart attacks and a high proportion of strokes,” commented Dr. Domingo Pascual-Figal, an external investigator at the CNIC and a cardiologist at the Hospital Universitario Virgen de Arrixaca in Murcia.

The study shows that clonal hematopoiesis is an important pathological process that accelerates and aggravates the clinical progression of heart failure, independently of the presence of atherosclerosis

Earlier experimental studies by CNIC scientists had also demonstrated that certain mutations that cause clonal hematopoiesis accelerate the development of atherosclerosis and the progression of heart failure symptoms in mice.

In the new study, which included input from the CNIC Genomics and Bioinformatics Units and investigators at Hospital Universitari Germans Trias i Pujol in Badalona (Barcelona), the research team analyzed how the presence of mutations linked to clonal hematopoiesis affects the clinical progression of patients with ischemic or non-ischemic heart failure

The scientists monitored the genomic DNA sequence of blood cells from the heart failure patients over many years to detect the presence of clonal hematopoiesis and assess its possible connection with the progression of their disease.  

Commenting on the results, Dr. Fuster said that, independently of the origin of heart failure, “the presence of these mutant blood-cell clones aggravates disease progression and worsens prognosis.”

Dr. Pascual-Figal explained that the specific study finding was that “clones with mutations in 2 genes frequently linked to clonal hematopoiesis, TET2 and DNMT3A, were associated with a higher risk of heart–failure-related hospitalization and death.”

For the researchers, these findings “demonstrate the importance of clonal hematopoiesis as a pathogenic process that accelerates and aggravates heart failure progression, independently of the presence of atherosclerosis.”

The authors conclude that their study supports the emerging idea that “clonal hematopoiesis represents a new cardiovascular risk factor and an important link between aging and cardiovascular disease.” The results, moreover, “open the way to the development of personalized therapies for patients with these somatic mutations, with the aim of preventing heart failure progression.”

The CNIC currently has several ongoing projects aimed at exploring the effects of somatic mutations and clonal hematopoiesis in more depth. The aim is to devise personalized strategies to prevent and treat patients with these mutations.

The study was funded by a Beca Leonardo para Investigadores y Creadores Culturales (2019) from the Fundación BBVA, the Carlos III Institute of Health, the Spanish Ministry of Science and Innovation, and the Fundación Séneca de Ciencia y Tecnología de la Región de Murcia.

Provided by CNIC

How Stem Cells Are Able to Generate New Blood Cells Throughout Our Life? (Medicine)

Princess Margaret scientists have revealed how stem cells are able to generate new blood cells throughout our life by looking at vast, uncharted regions of our genetic material that hold important clues to subtle biological changes in these cells.

Princess Margaret Cancer Centre Senior Scientist Dr. Mathieu Lupien and team used state-of-the-art 3D mapping techniques to analyze why some stem cells self-renew and others lose that ability. © Images By Delmar

The finding, obtained from studying normal blood, can be used to enhance methods for stem cell transplantation, and may also shed light into processes that occur in cancer cells that allow them to survive chemotherapy and relapse into cancer growth many years after treatment.

Using state-of-the art sequencing technology to perform genome-wide profiling of the epigenetic landscape of human stem cells, the research revealed important information about how genes are regulated through the three-dimensional folding of chromatin.

Chromatin is composed of DNA and proteins, the latter which package DNA into compact structures, and is found in the nucleus of cells. Changes in chromatin structure are linked to DNA replication, repair and gene expression (turning genes on or off).

The research by Princess Margaret Cancer Centre Senior Scientists Drs. Mathieu Lupien and John Dick is published in Cell Stem Cell, Wednesday, November 25, 2020.

“We don’t have a comprehensive view of what makes a stem cell function in a specific way or what makes it tick,” says Dr. Dick, who is also a Professor in the Department of Molecular Genetics, University of Toronto.

Princess Margaret Cancer Centre Senior Scientist Dr. John Dick and team have revealed how stem cells generate new blood cells throughout our lives, and also evade chemotherapy to survive and relapse many years later. (Photo: Images By Delmar)

“Stem cells are normally dormant but they need to occasionally become activated to keep the blood system going. Understanding this transition into activation is key to be able to harness the power of stem cells for therapy, but also to understand how malignant cells change this balance.

“Stem cells are powerful, potent and rare. But it’s a knife’s edge as to whether they get activated to replenish new blood cells on demand, or go rogue to divide rapidly and develop mutations, or lie dormant quietly, in a pristine state.”

Understanding what turns that knife’s edge into these various stem cell states has perplexed scientists for decades. Now, with this research, we have a better understanding of what defines a stem cell and makes it function in a particular way.

“We are exploring uncharted territory,” says Dr. Mathieu Lupien, who is also an Associate Professor in the Department of Medical Biophysics, University of Toronto. “We had to look into the origami of the genome of cells to understand why some can self-renew throughout our life while others lose that ability. We had to look beyond what genetics alone can tell us.”

In this research, scientists focused on the often overlooked noncoding regions of the genome: vast stretches of DNA that are free of genes (i.e. that do not code for proteins), but nonetheless harbour important regulatory elements that determine if genes are turned on or off.

Hidden amongst this noncoding DNA – which comprise about 98% of the genome – are crucial elements that not only control the activity of thousands of genes, but also play a role in many diseases.

The researchers examined two distinct human hematopoietic stem cells or immature cells that go through several steps in order to develop into different types of blood cells, such as white or red blood cells, or platelets.

They looked at long-term hematopoietic stem cells (HSCs) and short-term HSCs found in the bone marrow of humans. The researchers wanted to map out the cellular machinery involved in the “dormancy” state of long-term cells, with their continuous self-renewing ability, as compared to the more primed, activated and “ready-to-go” short-term cells which can transition quickly into various blood cells.

The researchers found differences in the three-dimensional chromatin structures between the two stem cell types, which is significant since the ways in which chromatin is arranged or folded and looped impacts how genes and other parts of our genome are expressed and regulated.

Using state-of-the-art 3D mapping techniques, the scientists were able to analyze and link the long-term stem cell types with the activity of the chromatin folding protein CTCF and its ability to regulate the expression of 300 genes to control long-term, self-renewal.

“Until now, we have not had a comprehensive view of what makes a stem cell function in a particular way,” says Dr. Dick, adding that the 300 genes represent what scientists now think is the “essence” of a long-term stem cell.

He adds that long-term dormant cells are a “protection” against malignancy, because they can survive for long periods and evade treatment, potentially causing relapse many years later.

However, a short-term stem cell that is poised to become active, dividing and reproducing more quickly than a long-term one, can gather up many more mutations, and sometimes these can progress to blood cancers, he adds.

“This research gives us insight into aspects of how cancer starts and how some cancer cells can retain stem-cell like properties that allow them to survive long-term,” says Dr. Dick.

He adds that a deeper understanding of stem cells can also help with stem cells transplants for the treatment of blood cancers in the future, by potentially stimulating and growing these cells ex vivo (out of the body) for improved transplantation.

The research was supported by The Princess Margaret Cancer Foundation, Ontario Institute for Cancer Research, Canadian Institutes for Health Research (CIHR), Medicine by Design, University of Toronto, Canadian Cancer Society Research Institute, and the Terry Fox Research Institute.

Provided by University Health Network

How Malaria Parasites Withstand A Fever’s Heat? (Medicine)

Even when a person suffering from malaria is burning up with fever and too sick to function, the tiny blood-eating parasites lurking inside them continue to flourish, relentlessly growing and multiplying as they gobble up the host’s red blood cells.

Malaria parasites at normal body temperature (left) and fever-like temperatures (right). A new study finds that the malaria parasite puts body armor around its ‘gut’ to withstand its human host’s raging fevers. ©Kuan-Yi Lu, Duke University

The single-celled Plasmodium parasites that cause 200 million cases of malaria each year can withstand feverish temperatures that make their human hosts miserable. And now, a Duke University-led team is beginning to understand how they do it.

Assistant professor of chemistry Emily Derbyshire and colleagues have identified a lipid-protein combo that springs into action to gird the parasite’s innards against heat shock.

Understanding how the malaria parasite protects its cells against heat stress and other onslaughts could lead to new ways to fight resistant strains, which have evolved ways to survive the drugs traditionally used to kill them, the researchers say.

Nearly half of the world’s population is at risk of contracting malaria. The disease kills 400,000 people a year, most of them children.

Long before the cause of malaria was identified, the disease’s harrowing fevers were well known. References to them have been found on 5,000-year-old clay tablets from ancient Mesopotamia. The Greek poet Homer wrote about their misery. Hippocrates too.

The Duke team, collaborating with professor of biological engineering Jacquin Niles at the Massachusetts Institute of Technology, wanted to know how the malaria parasites inside a person’s body make it through these fevers unscathed.

When the parasites enter a person’s bloodstream through the bite of an infected mosquito, the temperature around them jumps from the balmy mid-70s of the mosquito to 98.6 degrees in the human. The human host’s body temperature can then rocket to 105 degrees or higher before dropping back down to normal two to six hours later, a roller coaster pattern that repeats itself every two to three days.

“It’s like going from room temperature water to a hot tub,” said first author Kuan-Yi Lu, who earned his Ph.D. in molecular genetics and microbiology in Derbyshire’s lab at Duke.

For the paper, published Sept. 25 in the journal eLife, Lu spent hundreds of hours peering at parasites under the microscope, trying to figure out what happens inside them when temperatures seesaw.

To mimic malarial fever in the lab, the researchers placed malaria-infected red blood cells in an incubator heated to 104 degrees Fahrenheit for six hours before bringing them back down to normal body temperature, 98.6 degrees.

They found that when temperatures rise, the parasites produce more of a lipid molecule called phosphatidylinositol 3-phosphate, or PI(3)P.

This substance builds up in the outer wall of a tiny sac inside the parasite’s cells called the food vacuole — the protist’s version of a gut. There, it recruits and binds to another molecule, a heat shock protein called Hsp70, and together they help shore up the food vacuole’s outer walls.

Without this lipid-protein boost, the team found that heat can make the food vacuole start to leak, unleashing its acidic contents into the gel-like fluid that fills the cell and possibly even digesting the parasite from the inside.

The findings are important because they could help researchers make the most of existing malaria drugs.

Previous research has shown that malaria parasites with higher-than-normal PI(3)P levels are more resistant to artemisinins, the leading class of antimalarials. Since artemisinins were first introduced in the 1970s, partial resistance has been increasingly reported in parts of Southeast Asia, raising fears that we may be losing one of our best weapons against the disease.

But the Duke-led study raises the possibility that new combination therapies for malaria — artemisinins combined with other drugs that reduce the parasite’s PI(3)P lipid levels and disrupt the food vacuole’s membrane — could be a way to re-sensitize resistant parasites, breaking down their defenses so the malaria treatments we already have are effective again.

“If there is an alternative way to increase the permeability of the digestive vacuole, it could make the digestive vacuole more accessible to those drugs again,” Lu said.

The findings also suggest caution in giving malaria patients ibuprofen for fever if they’re already taking artemisinin-based compounds, Derbyshire said. That’s because artemisinins kill malaria parasites by damaging their cell’s survival machinery, including the machinery that makes PI(3)P. If artemisinins suppress PI(3)P levels, and thereby make malaria parasites more vulnerable to heat stress, then fever reducers could prolong the time it takes for artemisinin-based drugs to kill the parasites, as some reports have suggested.

Much remains to be learned, Derbyshire said. “There’s more work to do to establish the mode of action. But you could imagine designing new combination therapies to try and extend the life of artemisinin and prolong its effectiveness,” Derbyshire said.

References: Kuan-Yi Lu, Charisse Flerida A. Pasaje, Tamanna Srivastava, David R. Loiselle, Jacquin C. Niles, Emily R. Derbyshire, “Phosphatidylinositol 3-Phosphate and Hsp70 Protect Plasmodium Falciparum From Heat-Induced Cell Ceath,” eLife, Sept. 25, 2020. DOI: 10.7554/eLife.56773

Provided by Duke University