Tag Archives: macrophages

Immune cell gif.

Amazing video shows how white blood cells find pathogens — and points to a cure against cancer

Using cutting-edge microscopy imaging, researchers discovered — and filmed — the ‘sensors’ macrophage cells use to detect pathogens. The research might also yield one of the most powerful tools to date in the fight against cancer.

Immune cell gif.

Image credits University of Queensland / Youtube.

Macrophages form the first line of defense in our immune systems, patroling tissues throughout our bodies and guarding the bits susceptible to infection. Once a macrophage encounters something that doesn’t wear the protein tags of healthy human cells — such as cellular debris, pathogens, cancer cells, or foreign substances — the cell wraps around it and proceeds to digest it.

Still, despite decades of research, we still barely understand how macrophages — and their other white cell relatives — work. In an effort to patch our grasp of these mechanisms, a team from the University of Queensland (UQ) used cutting-edge microscopy techniques to film macrophage cells.

Their research led to the discovery of structures known as “tent-pole ruffles”, which underpin the cells’ functions. The same structures, the team writes, may help us find a new and very powerful tool against cancer.

If you can’t beat them, eat them

“It’s really exciting to be able to see cell behaviour at unprecedented levels of resolution,” says co-author Adam Wall, a researcher in molecular bioscience at UQ.

“This is discovery science at the cutting edge of microscopy and reveals how much we still have to learn about how cells function”.

The ruffles are located on the surface of macrophages, a specific type of white blood cell that directly engages pathogens and other undesirables in our bodies. Tent-pole ruffles underpin their function, the team writes, by allowing the cells to sample their surrounding fluids for potential threats.

Tent pole ruffles.

How tent-pole ruffles work — video below.
Image credits Nicholas D. Condon et al., 2018, JCB.

They take the name from their shape and work similarly to our sense of taste or smell: the ruffles extend from the cell’s body and — using a special membrane strung between the poles — gather relatively large volumes of fluid that are then sampled for chemical markers. This process is known as ‘macropinocytosis’. If any molecules from a foreign entity are detected, the cells move towards the source and prepare to engage.

Tent-pole ruffles are exceedingly small. Their discovery was only made possible by a new imaging technology known as ‘lattice light sheet microscopy’. The technique can capture tiny structures in a matter of seconds, generating stunning 3D renditions with very high precision.

“This imaging will give us phenomenal power to reveal how cell behaviour is affected in disease, to test the effects of drugs on cells, and to give us insights that will be important for devising new treatments,” says study supervisor Jenny Stow, a deputy director of research in molecular bioscience at UQ.

It’s a very fortunate development. The research helps us better understand how our immune systems scrub the body clean of pathogens, but it also points to a way to cripple cancer cells. These latter cells use the process of macropinocytosis to capture nutrients, not to probe their environment like the macrophages. Apart from that, the process works largely the same — tent-pole ruffles extend, the membranes capture field, and nutrients are absorbed.

In theory, then, if researchers can figure out how to destroy or inactivate the tent-pole ruffles of cancer cells, we could simply starve them out.

The team plans to continue using lattice light sheet microscopy to probe the natures of other human immune system cells.

The paper “Macropinosome formation by tent pole ruffling in macrophages” has been published in the Journal of Cell Biology.

Breast cancer cell.

Cell maps reveal how the body fights off cancer

Two new papers published in the journal Cell offer the first high-detail maps of the immune system cells which surround tumors.

Breast cancer cell.

Breast cancer cell seen under a scanning electron microscope.
Image credits National Cancer Institute.

The data could help guide research into new targets for cancer therapies and pinpoint biological markers which can be used to determine the likelihood of patients to respond to particular therapies or when best to start administering them.

What type of cells surround a tumor and the way they respond to it (especially immune system cells which bunch up at its border and fight towards the core) usually makes or breaks immunotherapy aimed at fighting the disease. Recent advances in the ability to characterize those individual cells are now driving a push to catalog and learn more about how the cells impact the progression of tumors.

Act faster, use more data

The first of the papers was published by a team led by Bernd Bodenmiller, a systems biologist at the University of Zurich, Switzerland. The team mapped the body’s immune response for clear cell renal cell carcinoma, a form of kidney cancer. The researchers focused on two types of immune cells — T cells and macrophages. Both of them are involved in either increasing or suppressing the body’s immune response to a tumor by altering the proteins they express.

Bodenmiller’s team worked with samples from 73 patients with kidney cancer and 5 samples from healthy individuals as a control group. They analyzed 3.5 million cells looking at the expression of 29 proteins used to characterize macrophages, and 23 to characterize T cells.

They found that the T cell populations and those of the macrophages were more varied than previously believed. They also note that patients with a particular combination of T cells and macrophages tended to have fast-progressive cancers. All in all, their results shows that the current practice of looking only at one or two major proteins to determine the state of a T cell or macrophage falls very short of giving oncologists the full picture.

The second study was led by oncologist Miriam Merad of the Icahn School of Medicine at Mount Sinai, New York City. His team compiled an atlas of immune cells associated with early-stage lung cancer. By comparing healthy lung tissue and blood with tumor tissue, they found that immune cells in the vicinity of tumors start to alter themselves since the early stages of the disease. This suggests that cancer treatments which target the immune system can be employed from the start, without having to wait for more advanced stages of the disease.

Understanding how our immune systems change in response to cancer would let doctors tailor our interventions against the disease to work in tandem with our bodies — so work like that performed by these two teams is hugely important for patients. The studies themselves are too small to change how we go about treating cancer right now — but they offer a wealth of possibilities. As more researchers double-check the findings and add new data on the foundation these two papers set in the coming years, we’re likely to see cancer treatments becoming more and more personalized.

The first paper “An Immune Atlas of Clear Cell Renal Cell Carcinoma” has been published in the journal Cell. The second paper “Innate Immune Landscape in Early Lung Adenocarcinoma by Paired Single-Cell Analyses” has been published in the journal Cell as well.

Bacteriophages (green) attacking a bacterium (orange). Credit: Graham Beards.

Patient saved from antibiotic-resistant infection with novel bacteriophage treatment

An experimental therapy using bacteriophages (viruses of bacteria) successfully cured a patient of a multi-drug resistant bacterial infection. No antibiotic, no matter how strong, could help the patient who had been in a coma for two years. The findings suggest that personalized phage therapy can be very successful and will likely propel more research groups to devote more resources for such life-saving initiatives. The World Health Organization estimates that by 2050, 50 million people will die because of antibiotic-resistant infections. No new class of antibiotics has been discovered in the last three decades.

When bacteria resist

In late 2015, Tom Petterson,  a 69-year-old professor in the Department of Psychiatry at UC San Diego School of Medicine, was vacationing with his wife in Egypt when he suddenly became ill. Local doctors quickly diagnosed him with pancreatitis, an inflammation of the pancreas, and when standard care failed he was urgently flown to Frankfurt, Germany. There, doctors found he had been infected with a multidrug-resistant strain of Acinetobacter baumannii. 

The German doctors also discovered a pancreatic pseudocyst which causes fluid to build up around the pancreas. Antibiotics seemed to fail. The only thing that worked was a drug of last resort — a mix of meropenem, tigecycline, and colistin, which is known to cause kidney damage among its many side effects. The situation warranted this extreme measure, though, and once his condition became stable enough, Patterson was flown to the Thornton Hospital at UC San Diego Health. Here disaster waited. The doctors found that upon arrival the bacteria had become resistant to all antibiotics.

To make matters worse, as Patterson was prepared for transfer to a long-term acute care facility, an internal drain slipped, spilling bacteria into his abdomen and bloodstream. The patient immediately entered in septic shock and soon after fell into a coma. He would stay in a coma for the next two months. His days were numbered but family and colleagues at the university didn’t stay idle.

“There came a point when he was getting weaker and weaker, and I didn’t want to lose him. I wasn’t ready to let him go and so I held his hand and said, ‘Honey, they’re doing everything they can and there’s nothing that can kill this bug, so if you want to fight, you need to fight. Do you want me to find some alternative therapies? We can leave no stone unturned,'” the patient’s wife, Steffanie Strathdee, recalled. Strathdee is the chief of the Division of Global Public Health in the Department of Medicine at UC San Diego and no stranger to crippling diseases.

Two can play this game: infecting bacteria

Bacteriophages (green) attacking a bacterium (orange). Credit: Graham Beards.

Bacteriophages (green) attacking a bacterium (orange). Credit: Graham Beards.

Strathdee read everything she got her hands on. While researching, she was informed about a case from Tblisi, Georgia where a patient suffering from a ‘difficult’ infection was ‘miraculously cured’ after undergoing phage therapy.

Bacteriophages are viruses, and the most numerous kind to boot. By some estimates, there are 1031 bacteriophages on the planet or more than every other organism on Earth combined. That includes bacteria. If bacteria infects humans, bacteriophages infect the bacteria. These phages cause a trillion trillion successful infections per second and destroy up to 40 percent of all bacterial cells in the ocean every day.

Bacteriophages were formally discovered in the mid to late teens of the 20th century, with the first publication coming out in 1915. In the 1920s and the 1930s, phage therapy was commonly used to treat various bacterial infections but as antibiotics became more widespread and easy to use, phage therapy turned into a simple mention in medical textbooks. Some parts of Eastern Europe and the Soviet Union were still involved with phage therapy research, it’s worth adding.

More than a hundred years since phage therapy was described, the joke’s on us. Countless strains of bacteria are becoming resistant to antibiotics. Common STDs like gonorrhea will become untreatable in the next decade by some accounts, and mortality because of multi-drug bacterial infections will become widespread. Already, hundreds of thousands of people around the world die from hospital-acquired multi-drug resistant bacteria and the World Health Organization estimates antimicrobial resistance will kill at least 50 million people per year by 2050.

Though obscure, Strathdee managed to come across people who were working with phage therapy. They found three team with phages that could target Patterson’s specific infection: the Biological Defense Research Directorate of the NMRC in Frederick, MD; the Center for Phage Technology at Texas A&M University; and AmpliPhi, a San Diego-based biotech company specializing in bacteriophage-based therapies. All three agreed to help and the phage samples were sent to San Diego State University where they were purified. Meanwhile, emergency approval for the samples’ use was given by the Food and Drug Administration.

Against all odds

Patterson was given the phages through catheters into his abdominal cavity and intravenously so the therapy acted more broadly. Patterson’s condition began to improve and within three days since the first IV phage therapy, he had emerged from his long coma.

“As a treating doctor, it was a challenge,” said Chip Schooley, one of Strathdee’s colleagues. “Usually you know what the dosage should be, how often to treat. Improving vital signs is a good way to know that you’re progressing, but when you’re doing it for the first time, you don’t have anything to compare it to.

“A lot was really worked out as we went along, combining previous literature, our own intuition about how these phages would circulate and work and advice from people who had been thinking about this for a long time.”

Patterson described the experience as miraculous, though his body had been severely weakened after losing 100 pounds in coma, mostly muscle.

“The phage therapy has really been a miracle for me, and for what it might mean that millions of people who may be cured from multidrug-resistant infections in the future. It’s been sort of a privilege,” Patterson confessed.

Though the sample size of the study only measures one person, Patterson’s case study gives hope that personalized therapy with bacteriophages can undo possibly any infection where antibiotics don’t work. Most people around the world won’t have Patterson’s privilege of having friends and family who are among the best doctors in the world. It will be an immense challenge to translate this sort of therapy into something that’s as easy and cheap as antibiotics are today. Well, cheap and easy for now at least.