HIV virus in disguise tricks immune system, Marie Larsson is Professor of Molecular Virology

Name: Marie LarssonTitle: Professor of Molecular Virology
Department: IKE

CONTACT

Phone: +46 (0)10-103 10 55
E-mail: marie.larsson@liu.se

Address:
Linköping University
Department of Clinical and Experimental Medicine
Virology
SE-581 85 Linköping
Sweden

Marie Larsson is Professor of Molecular Virology. Her research is in the area of immunovirology, specifically HIV research with focus on the immunomodulatory effect this virus has on dendritic cells and T cells. She has also ongoing projects exploring new adjuvants and vaccine constellations for cancer and virus. Furthermore, she is investigating the induction and sustainment of cancer associated inflammation and the deleterious effect this has on host immune defense.

Immunomodulatory effects of HIV-1’s interactions with DCs and T cells from

blood and mucosa
So far over 30 million people have died from HIV-1 infection (figure 1), the majority of them in the developing countries, and this epidemic is still cause for major concern. The existing antiretroviral therapy dampens the infection and the destruction of the immune system, i.e. AIDS, but does not cure the disease. Sadly, this therapy is not available to all HIV infected and is a very expensive lifelong commitment with severe side effects.

A vaccine blocking HIV infection is theDendritic cell sought-after solution but there is no hope that we will have such a vaccine in the near future. Instead we can hope for a therapy that induces a potent long lasting immune response consisting of CD4+ and CD8+ T cells, two types of control cells involved in the immune defense, that have proven to be important to control the infection. There exists a unique cell in all tissues in our bodies, the dendritic cell (DC) (Figure 2) with unique ability to activate T cells so they can perform their job in the body. DCs in the vaginal and rectal tissues are one of the first cells to encounter HIV during intercourse with an infected individual (Figure 3 and 4). Unfortunately, HIV hijacks the DCs, which makes this cell responsible for spreading the virus to interacting T cells in the body which provokes HIV-infection of T cells and cell death when it should be initiating immune responses to fight the infection.DC HIV

My research aspires to elucidate the mechanisms behind the immunomodulatory effects HIV exerts on DCs and on their ability to activate T cells. Focus will be on; Elucidation of the mechanisms involved in HIV’s binding to and uptake by DCs and the subsequent degradation that leads to DC antigen presentation of HIV peptides for activation of HIV specific T cells. Elucidation of the mechanisms responsible for the negative effects HIV exerts on DCs and if presence of HIV virions during DC T cell priming impairs the T cell function. Elucidate the effect opsonized HIV-1 exerts on immune cells such as DCs, NK cells and T cells. Identification of receptors and cells involved in the initial HIV infection of cervical mucosa and colorectal mucosa,  and potential microbiocides that can block the initial infection, and elucidation of why HIV affects the T cells in the gut to a higher extent than the T cells in blood.

HIV will continue to kill people and have a great impact on mankind until we have a drug that can stop this infection. My ambition is that the planed research will answer some basic questions regarding the role of DCs in HIV pathogenesis and induction of potent immune response against this virus. This knowledge will guide how a vaccine/therapy needs to be constructed in order to have high efficacy.

                                                             Mucosal transmission

                                                                Cervix

Cancer research

Elucidation the role of IL-1α and the microenvironment in development of pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is a common gastrointestinal malignancy with an exceptional poor prognosis and a mortality rate that nearly matches the rate of incidence. The cross-talk between PDAC and stroma cells, e.g. cancer associated fibroblasts (CAF), and immune cells, may create an environment with chronic inflammation augmenting tumor transformation and maintenance.

In PDAC, more than 70% of the total tumor mass can consist of fibrotic stroma, which makes CAFs the major component in this cancer. PDAC inflammatory environment consists of many mediators, e.g. IL-1, COX-2, IL-6, and CXCL8, and some of these factors correlate to tumor development and poor prognosis. Of note, elevated expression of IL-1 in tumors has been associated with more aggressive disease. Several studies, including ours have reported that dendritic cells (DCs), one of the immune cells found in the tumor microenvironment, show phenotypic and functional abnormalities when isolated from tumor bearing animals and individuals with PDAC. Recent findings provided some evidence that the COX-2 metabolite PGE2 is involved in the upregulation of immunomodulatory factors in DCs impairing their T cell stimulatory ability. The aims are to examine the receptor-ligands and signaling pathways involved in the cross talk between stroma cells, i.e. CAFs, and PDAC cells giving rise to the inflammatory environment and creating an environment sustaining the PDAC. To examine the role IL-1 cytokine family and effects these cytokines cell signaling have on creating the inflammatory environment and in tumor development and survival. To examine whether neutralization of IL1 signaling pathway enhances the survival and quality of life for individuals with pancreatic cancer.

The information gained from the proposed research will help us understand the mechanisms underlying the development of PDAC and the effect this solid tumor exert on the body and may help designing therapies for PDAC.

Source: Linköping University

Scheduling tool a big help in healthcare

The HIV virus avoids the body’s immune cells by disguising itself using proteins that normally take part in the defence against infections. These are the findings of research conducted at the Division of Molecular Virology.

Professor Marie LarssonThese “complement proteins” are soluble molecules that attach themselves to foreign particles and those of the body in different patterns. These patterns help the immune system to identify and attack dangerous intruders such as viruses and bacteria.

Phd student Rada EllegårdInstead, HIV exploits the complement proteins present in all body fluids in order to make its way into the body tissues without being attacked. It was known previously that infections are much more effective if the virus is surrounded by the bodily fluids normally present in blood or sexual contagion than if it is isolated in a laboratory environment. In an article in the Journal of Immunology Marie Larsson, professor of molecular virology (left) and PhD student Rada Ellegård (right) provide an explanation of this phenomenon.

“The ability to use our complement proteins in this way is probably key to the success of HIV in being transmitted. We are currently carrying out further work to investigate these mechanisms in the male genital mucous membrane – the tissue where the virus infection takes place in sexual transmission,” says Ms Larsson.

The first thing HIV particles come into contact with is dendritic cells, immune cells that function as sentry posts. Their job is to identify viruses as dangerous and hostile to the body, and to respond by producing the substances that combat infections and moving to a lymph node to set a specific immune defence in motion.

In the case of HIV, this process does not seem to work very well. The disguise stops the dendritic cells recognising the virus, which instead establishes an infection in the mucous membrane and uses the movement to the lymph nodes as a way to spread around the whole body.

As more and more cells are infected and killed, the virus slowly breaks down our immune system. Without treatment this sequence of events leads to AIDS, a condition where the victim becomes extremely vulnerable to infection and where normally harmless viruses and bacteria become life-threatening.

Related content

Marie Larsson - research presentation >>

                                       HIV-illustration

When a virus is captured by a dendritic cell, it is recognised by a virus sensor that normally sets in motion infection reduction factors which inhibit the production of new virus particles (picture, left). HIV has the ability to clothe itself in complements, a type of protein present in our bodily fluids. In this way it can dampen the signals from the virus sensors and produce many new particles (picture, right).


Source: Linköping University

Transplant drug could boost power of brain tumor treatments, study finds

Drs. Maria Castro and Pedro Lowenstein, both of the U-M Department of Neurosurgery, co-led the research. Credit: Image courtesy of University of Michigan Health System

Every day, organ transplant patients around the world take a drug called rapamycin to keep their immune systems from rejecting their new kidneys and hearts. New research suggests that the same drug could help brain tumor patients by boosting the effect of new immune-based therapies.

In experiments in animals, researchers from the University of Michigan Medical School showed that adding rapamycin to an immunotherapy approach strengthened the immune response against brain tumor cells.

What's more, the drug also increased the immune system's "memory" cells so that they could attack the tumor if it ever reared its head again. The mice and rats in the study that received rapamycin lived longer than those that didn't.

Now, the U-M team plans to add rapamycin to clinical gene therapy and immunotherapy trials to improve the treatment of brain tumors. They currently have a trial under way at the U-M Health System which tests a two-part gene therapy approach in patients with brain tumors called gliomas in an effort to get the immune system to attack the tumor. In future clinical trials, adding rapamycin could increase the therapeutic response.

The new findings, published online in the journal Molecular Cancer Therapeutics, show that combining rapamycin with a gene therapy approach enhanced the animals' ability to summon immune cells called CD8+ T cells to kill tumor cells directly. Due to this cytotoxic effect, the tumors shrank and the animals lived longer.

But the addition of rapamycin to immunotherapy even for a short while also allowed the rodents to develop tumor-specific memory CD8+ T cells that remember the specific "signature" of the glioma tumor cells and attacked them swiftly when a tumor was introduced into the brain again.

"We had some indication that rapamycin would enhance the cytotoxic T cell effect, from previous experiments in both animals and humans showing that the drug produced modest effects by itself," says Maria Castro, Ph.D., senior author of the new paper. Past clinical trials of rapamycin in brain tumors have failed.

"But in combination with immunotherapy, it became a dramatic effect, and enhanced the efficacy of memory T cells too. This highlights the versatility of the immunotherapy approach to glioma." Castro is the R.C. Schneider Collegiate Professor of neurosurgery and a professor of cell and developmental biology at U-M.

Rapamycin is an FDA-approved drug that produces few side effects in transplant patients and others who take it to modify their immune response. So in the future, Castro and her colleagues plan to propose new clinical trials that will add rapamycin to immune gene therapy trials like those already ongoing at UMHS.

She notes that other researchers currently studying immunotherapies for glioma and other brain tumors should also consider doing the same. "This could be a universal mechanism for enhancing efficacy of immunotherapies in glioma," she says.

Rapamycin inhibits a specific molecule in cells, called mTOR. As part of the research, Castro and her colleagues determined that brain tumor cells use the mTOR pathway to hamper the immune response of patients.

This allows the tumor to trick the immune system, so it can continue growing without alerting the body's T cells that a foreign entity is present. Inhibiting mTOR with rapamycin, then, uncloaks the cells and makes them vulnerable to attack.

Castro notes that if the drug proves useful in human patients, it could also be used for long-term prevention of recurrence in patients who have had the bulk of their tumor removed. "This tumor always comes back," she says.

Source: University of Michigan Health System

3-D culture system for pancreatic cancer has potential to change therapeutic approaches

A team of researchers has developed a method to grow pancreatic tissue in a three-dimensional culture system, called organoids. The scientists are able to use tissue not only from laboratory mouse models, but also from human patients. The technology promises to change the way pancreatic cancer research is done, offering a path to personalized treatment approaches in the future. Credit: D. Tuveson/ Cold Spring Harbor Laboratory

Cold Spring Harbor and Bethpage, N.Y. -- Pancreatic cancer is one of the most deadly forms of cancer, with only 6 percent of patients surviving five years after diagnosis. Today, Cold Spring Harbor Laboratory (CSHL) and The Lustgarten Foundation jointly announce the development of a new model system to grow both normal and cancerous pancreatic cells in the laboratory. Their work offers the potential to change the way pancreatic cancer research is done, allowing scientists to interrogate the pathways driving this devastating disease while searching for new drug targets.

In work published in Cell, the research team describes a three-dimensional "organoid" culture system for pancreatic cancer. Co-led by David Tuveson, CSHL Professor and Director of Research for The Lustgarten Foundation, and Hans Clevers, Professor and Director of the Hubrecht Institute and President of the Royal Netherlands Academy of Arts and Sciences, the team developed a method to grow pancreatic tissue not only from laboratory mouse models, but also from human patient tissue, offering a path to personalized treatment approaches in the future.

All cancer research relies on a steady supply of cells -- both normal and cancerous -- that can be grown in the laboratory. By comparing normal cells to cancer cells, scientists can then identify the changes that lead to disease. However, both types of pancreatic cells have been extremely difficult to culture in the laboratory.

Furthermore, the normal ductal cells that are able to develop into pancreatic cancer represent about 10 percent of the cells in the pancreas, complicating efforts to pinpoint the changes that occur as the tumor develops. Until now, scientists have been entirely unable to culture human normal ductal pancreatic cells under standard laboratory conditions. 

Because of these limitations, most pancreatic cancer research relies on genetically engineered mouse models of the disease, which can take up to one year to generate. "With this development, we are now able to culture both mouse and human organoids, providing a very powerful tool in our fight against pancreatic cancer," explains Tuveson.

The organoids are entirely made up of ductal cells, eliminating the surrounding cell types that often contaminate samples from the pancreas. They grow as hollow spheres within a complex gel-like substance filled with growth-inducing factors and connecting fibers. Once they have grown to a sufficient size, the organoids can be transplanted back into mice, where they fully recapitulate pancreatic cancer. "We now have a model for each stage in the progression of the disease," says Chang-Il Hwang, Ph.D., one of the lead authors working in The Lustgarten Foundation's Pancreatic Cancer Research Lab at CSHL directed by Dr. Tuveson.

Traditionally, cancer cells are isolated during surgery or autopsies. Unfortunately, approximately 85 percent of cancer patients are ineligible for surgery at the time of diagnosis, either because the tumor is entwined in critical vasculature or the disease has progressed too far. Researchers therefore have had limited access to patient samples. The new research provides a way for scientists to grow organoids from biopsy material, which is comparatively easy to obtain. "Biopsies are the standard for diagnosis," says Dannielle Engle, Ph.D., also a lead author on the paper. "We can now rapidly generate organoids from any patient, which offers us the potential to study the disease in a much wider population."

The team is now working to create a repository of pancreatic tumor samples, coordinating with the National Cancer Institute. "We hope to make this available to the entire pancreatic cancer research community," says Tuveson. Additionally, Lindsey Baker, Ph.D., another lead author of the paper, has started holding an "organoid school" for other researchers, and has already taught six laboratories from around the world this technique.

Source: Cold Spring Harbor Laboratory

First steps in formation of pancreatic cancer identified

Shown is a region of a pancreas with preneoplastic lesions. Red labeling indicates macrophages, green labeling indicates pancreatic acinar cells that dedifferentiate, and grey labeling indicates further progressed pancreatic lesions. Credit: Image courtesy of Mayo Clinic

Researchers at Mayo Clinic's campus in Jacksonville say they have identified first steps in the origin of pancreatic cancer and that their findings suggest preventive strategies to explore.

In an online issue of Cancer Discovery, the scientists described the molecular steps necessary for acinar cells in the pancreas -- the cells that release digestive enzymes -- to become precancerous lesions. Some of these lesions can then morph into cancer.

"Pancreatic cancer develops from these lesions, so if we understand how these lesions come about, we may be able to stop the cancer train altogether," says the study's lead investigator, Peter Storz, Ph.D., a cancer biologist.

The need for new treatment and prevention strategies is pressing, Dr. Storz says. Pancreatic cancer is one of the most aggressive human cancers -- symptoms do not occur until the cancer is well advanced. One-year survival after diagnosis is only 20 percent. It is the fourth leading cause of cancer death in this country.

The scientists studied pancreatic cells with Kras genetic mutations. Kras produces a protein 

that regulates cell division, and the gene is often mutated in many cancers. More than 95 percent of pancreatic cancer cases have a Kras mutation.

The researchers detailed the steps that led acinar cells with Kras mutations to transform into duct-like cells with stem cell-like properties. Stem cells, which can divide at will, are also often implicated in cancer.

They found that Kras proteins in the acinar cells induce the expression of a molecule, ICAM-1, which attracts macrophages, a specific kind of immune cells. These inflammatory macrophages release a variety of proteins, including some that loosen the structure of the cells, allowing acinar cells to morph into different types of cells. These steps produced the precancerous pancreatic lesions.

"We show a direct link between Kras mutations and the inflammatory environment that drive the initiation of pancreatic cancer," Dr. Storz says.

But the process can be halted in laboratory mice, he adds. "We could do this two ways -- by depleting the macrophages or by treating the transformed cells with a blocking antibody that shuts down ICAM-1," says Dr. Storz. "Doing either one reduced the number of precancerous lesions."

Dr. Storz noted that a neutralizing antibody that blocks ICAM-1has already been developed. It is being tested for a wide variety of disorders, including stroke and rheumatoid arthritis.

"Understanding the crosstalk between acinar cells with Kras mutations and the microenvironment of those cells is key to developing targeted strategies to prevent and treat this cancer," he says.

Source: Mayo Clinic

Understanding, improving body's fight against pathogens

Significant reductions in the number of plasma cells in the spleen and bone marrow were observed in the absence of DOK3. Each dot in the figure represents one plasma cell detected. Credit: Image courtesy of A*Star Agency for Science, Technology and Research

Scientists from A*STAR's Bioprocessing Technology Institute (BTI) have uncovered the crucial role of two signalling molecules, DOK3 and SHP1, in the development and production of plasma cells. These discoveries, published in two journals PNAS and Nature Communications, advance the understanding of plasma cells and the antibody response, and may lead to optimisation of vaccine development and improved treatment for patients with autoimmune diseases such as lupus and tumours such as multiple myeloma.

While they exist in small populations in humans, the large amounts of antibodies secreted by plasma cells make them key to the body's immune system and its ability to defend itself against pathogens, such as bacteria and viruses. Proper maintenance of a pool of plasma cells is also critical for the establishment of lifelong immunity elicited by vaccination.

Dysregulation of plasma cell production and maintenance could lead to autoimmune diseases and multiple myeloma. Autoimmune diseases occur when the immune system does not distinguish between healthy tissue and antigens, which are found in pathogens. This results in expansion of plasma cells which produce excessive amounts of antibodies leading to destruction of one's own healthy tissue. The discoveries by scientists in BTI's Immunology Group have improved understanding of the mechanism by which plasma cells are developed from a major class of white blood cells called B cells.

For the first time, the molecule DOK3 was found to play an important role in formation of plasma cells. While calcium signalling typically controls a wide range of cellular processes that allow cells to adapt to changing environments, it was found to inhibit the expression of the membrane proteins essential for plasma cell formation. These membrane proteins include PDL1 and PDL2, and represent some of the key targets for the development of immunotherapy by pharmaceutical companies. DOK3 was able to promote the production of plasma cells by reducing the effects of calcium signalling on these membrane proteins. The absence of DOK3 would thus result in defective plasma cell formation.

In another study, BTI scientists discovered the importance of SHP1 signalling to the long term survival of plasma cells. While the molecule SHP1 has a proven role in prevention of autoimmune diseases, it was found that the absence of SHP1 would result in the failure of plasma cells to migrate from the spleen where they are generated to the bone marrow, a survival niche where they are able to survive for much longer periods. This could result in a reduction of the body's immune response and thus, an increased susceptibility to infections and diseases. The scientists in this study also successfully rectified the defective immune response caused by an absence of SHP1 by applying antibody injections, which might advance the development of therapeutics. On the other hand, targeting SHP1 might be a strategy to treat multiple myeloma where the accumulation of cancerous plasma cells in the bone marrow survival niches is undesirable.

Findings hold potential for improved treatment

The discovery of these new targets for modulating the antibody response allows the development of novel therapeutic strategies for patients with autoimmune diseases and cancer.Understanding the mechanism that governs plasma cell differentiation is also critical for the optimal design of vaccines and adjuvants, which are added to vaccines to boost the body's immune response.

Prof Lam Kong Peng, Executive Director of BTI, said, "These findings allow better understanding of plasma cells and their role in the immune system. The identification of these targets not only paves the way for development of therapeutics for those with autoimmune diseases and multiple myeloma, but also impacts the development of immunological agents for combating infections."

Source: A*Star Agency for Science, Technology and Research

Shape of things to come in platelet mimicry

By mimicking the shape, size, flexibility and surface chemistry of real platelets, artificial platelets are pushed out of the main blood flow to vessel walls. There, the surface chemistry enables them to anchor on damaged cells and induce faster clotting at the site. Credit: Anirban Sen Gupta

Artificial platelet mimics developed by a research team from Case Western Reserve University and University of California, Santa Barbara, are able to halt bleeding in mouse models 65 percent faster than nature can on its own.

For the first time, the researchers have been able to integratively mimic the shape, size, flexibility and surface chemistry of real blood platelets on albumin-based particle platforms. The researchers believe these four design factors together are important in inducing clots to form faster selectively at vascular injury sites while preventing harmful clots from forming indiscriminately elsewhere in the body.

The new technology, reported in the journal ACS Nano, is aimed at stemming bleeding in patients suffering from traumatic injury, undergoing surgeries or suffering clotting disorders from platelet defects or a lack of platelets. Further, the technology may be used to deliver drugs to target sites in patients suffering atherosclerosis, thrombosis or other platelet-involved pathologic conditions.

Anirban Sen Gupta, an associate professor of biomedical engineering at Case Western Reserve, previously designed peptide-based surface chemistries that mimic the clot-relevant activities of real platelets. Building on this work, Sen Gupta now focuses on incorporating morphological and mechanical cues that are naturally present in platelets to further refine the design.

"Morphological and mechanical factors influence the margination of natural platelets to the blood vessel wall, and only when they are near the wall can the critical clot-promoting chemical interactions take place," he said.

These natural cues motivated Sen Gupta to team up with Samir Mitragotri, a professor of chemical engineering at UC Santa Barbara, whose laboratory has recently developed albumin-based technologies to make particles that mimic the geometry and mechanical properties of red blood cells and platelets.

Together, the team has developed artificial platelet-like nanoparticles (PLNs) that combine morphological, mechanical and surface chemical properties of natural platelets.

The researchers believe this refined design will be able to simulate natural platelet's ability to collide effectively with larger and softer red blood cells in systemic blood flow. The collisions cause margination -- pushing the platelets out of the main flow and closer to the blood vessel wall -- increasing the probability of interacting with an injury site.

The surface coatings enable the artificial platelets to anchor to injury-site-specific proteins, von Willebrand Factor and collagen, while inducing the natural and artificial platelets to aggregate faster at the injury site.

Testing in mouse models showed that intravenous injection of these artificial platelets formed clots at the site of injury three times faster than natural platelets alone in control mice.

The ability to interact selectively with injury site proteins, as well as the ability to remain mechanically flexible like natural platelets, enables these artificial platelets to safely ride through the smallest of blood vessels without causing unwanted clots.

Albumin, a protein found in blood serum and eggs, is already used with cancer drugs and considered a safe material. Artificial platelets that don't become involved in a clot and continue to circulate are metabolized within one to two days.

The researchers believe the new artificial platelet design may be even more effective in larger volume blood flows where margination to the blood vessel wall is more prominent. They expect to soon begin testing those capabilities.

This research was previously funded by American Heart Association and is currently funded by National Institutes of Health.

In addition to stemming bleeding, Sen Gupta believes the technology could also be useful in delivering clot-busting medicines directly to clots, to treat heart attack or stroke without having to systemically suspend the body's coagulation mechanism. The artificial platelets may also be used to deliver cancer medicines to metastatic tumors that have high platelet interactions. Sen Gupta is seeking grants to pursue that work.

Source: Case Western Reserve University

Platelet-like particles augment natural blood clotting for treating trauma

Associate Professor Tom Barker and Research Scientist Ashley Brown examine bacteria growing on a plate, part of a technique for evolving antibodies in their work on platelet-like particles.
Credit: Georgia Tech Photo

A new class of synthetic platelet-like particles could augment natural blood clotting for the emergency treatment of traumatic injuries -- and potentially offer doctors a new option for curbing surgical bleeding and addressing certain blood clotting disorders without the need for transfusions of natural platelets.

The clotting particles, which are based on soft and deformable hydrogel materials, are triggered by the same factor that initiates the body's own clotting processes. Testing done in animal models and in a simulated circulatory system suggest that the particles are effective at slowing bleeding and can safely circulate in the bloodstream. The particles have been tested with human blood, but have not undergone clinical trials in humans.

Supported by the National Institutes of Health, the U.S. Department of Defense, and the American Heart Association, the research will be reported September 7, 2014, in the journal Nature Materials. Researchers from the Georgia Institute of Technology, Emory University, Children's Healthcare of Atlanta and Arizona State University collaborated on the research.

"When used by emergency medical technicians in the civilian world or by medics in the military, we expect this technology could reduce the number of deaths from excessive bleeding," said Ashley Brown, a research scientist in the Georgia Tech School of Chemistry and Biochemistry and first author of the paper. "If EMTs and medics had particles like these that could be injected and then go specifically to the site of a serious injury, they could help decrease the number of deaths associated with serious injuries."

The bloodstream contains proteins known as fibrinogen that are the precursors for fibrin, the polymer that provides the basic structure for natural blood clots. When they receive the right signals from a protein known as thrombin, these precursors polymerize at the site of the bleeding. The synthetic platelet-like particles use the same trigger, and so are activated only when the body's natural clotting process is initiated.

To create that trigger, the researchers followed a process known as molecular evolution to develop an antibody that could be attached to the hydrogel particles to change their form when they encounter thrombin-activated fibrin. The resulting antibody has a high affinity for the polymerized form of fibrin and a low affinity for the precursor material.

"Fibrin production is on the back end of the clotting process, so we feel that it is a safer place to try to interact with it," said Tom Barker, an associate professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University, and one of the paper's co-corresponding authors. "The specificity of this material provides a very important advantage in triggering clotting at just the right time."

The effectiveness of the platelet-like particles has been tested in an animal model and in a microfluidic chamber designed to simulate conditions within the body's circulatory system. In the chamber, tubes about the thickness of a human hair were lined with endothelial cells as in natural blood vessels.

The chamber was used to study normal human blood, as well as human blood that had been depleted of its natural platelets. In platelet-rich blood, clots formed as expected, and blood without platelets did not form clots. When the platelet-like particles were added to the platelet-depleted blood, it was able to clot.

The researchers also tested blood from infants that had undergone open heart surgery, which requires that their blood be diluted, reducing its clotting ability. When platelet-like particles were added to the dilute neonate blood, it was able to form clots.

Finally, safety testing was done on blood from hemophiliac patients. Because that blood lacks the triggers needed to cause fibrin formation, the particles had no effect. Before they can be used in humans, the particles will have to undergo human trials and receive clearance from the U.S. Food & Drug Administration (FDA).

About one micron in diameter, the particles were originally developed to be used on the battlefield by wounded soldiers, who might self-administer them using a device about the size of a smartphone. But the researchers believe the particles could also reduce the need for platelet transfusions in patients undergoing chemotherapy or bypass surgery, and in those with certain blood disorders.

"For a patient with insufficient platelets due to bleeding or an inherited disorder, physicians often have to resort to platelet transfusions, which can be difficult to obtain," said Dr. Wilbur Lam, another of the paper's co-authors and a physician in the Aflac Cancer and 
Blood Disorders Center at Children's Healthcare of Atlanta and the Department of Pediatrics at the Emory University School of Medicine. "These particles could potentially be a way to obviate the need for a transfusion. Though they don't have all the assets of natural platelets, a number of intriguing experiments have shown that the particles help augment the clotting process."

In addition to providing new treatment options, the particles could also cut costs by reducing costly natural transfusions, said Lam, who is also an assistant professor in the Coulter Department of Biomedical Engineering at Georgia Tech and Emory University.

What ultimately happens to the hydrogel particles circulating in the bloodstream will be the topic of future research, noted Brown. Particles of similar size and composition are normally eliminated from the body.

While the platelet-like particles lack many features of natural platelets, the researchers were surprised to find one property in common. Clots formed by natural platelets begin to contract over a period of hours, beginning the body's repair process. Clots formed from the synthetic particles also contract, but over a longer period of time, Brown noted.

Source: Georgia Institute of Technology

Cold virus replicates better at cooler temperatures

Artist's rendering of a rhinovirus (stock illustration). Credit: © fotoliaxrender / Fotolia

The common cold virus can reproduce itself more efficiently in the cooler temperatures found inside the nose than at core body temperature, according to a new Yale-led study. This finding may confirm the popular yet contested notion that people are more likely to catch a cold in cool-weather conditions.

Researchers have long known that the most frequent cause of the common cold, the rhinovirus, replicates more readily in the slightly cooler environment of the nasal cavity than in the warmer lungs. However, the focus of prior studies has been on how body temperature influenced the virus as opposed to the immune system, said study senior author and Yale professor of immunobiology Akiko Iwasaki.

To investigate the relationship between temperature and immune response, Iwasaki and an interdisciplinary team of Yale researchers spearheaded by Ellen Foxman, a postdoctoral fellow in Iwasaki's lab, examined the cells taken from the airways of mice. They compared the immune response to rhinovirus when cells were incubated at 37 degrees Celsius, or core body temperature, and at the cooler 33 degrees Celsius. "We found that the innate immune response to the rhinovirus is impaired at the lower body temperature compared to the core body temperature," Iwasaki said.

The study also strongly suggested that the varying temperatures influenced the immune response rather than the virus itself. Researchers observed viral replication in airway cells from mice with genetic deficiencies in the immune system sensors that detect virus and in the antiviral response. They found that with these immune deficiencies, the virus was able to replicate at the higher temperature. "That proves it's not just virus intrinsic, but it's the host's response that's the major contributor," Iwasaki explained.

Although the research was conducted on mouse cells, it offers clues that may benefit people, including the roughly 20% of us who harbor rhinovirus in our noses at any given time. "In general, the lower the temperature, it seems the lower the innate immune response to viruses," noted Iwasaki. In other words, the research may give credence to the old wives' tale that people should keep warm, and even cover their noses, to avoid catching colds.

Yale researchers also hope to apply this insight into how temperature affects immune response to other conditions, such as childhood asthma. While the common cold is no more than a nuisance for many people, it can cause severe breathing problems for children with asthma, noted Foxman. Future research may probe the immune response to rhinovirus-induced asthma.

The study was published in the Proceedings of the National Academy of Sciences.

Source: Yale University

Novel approach to treating asthma: Neutralize the trigger

Current asthma treatments can alleviate wheezing, coughing and other symptoms felt by millions of Americans every year, but they don't get to the root cause of the condition. Now, for the first time, scientists are reporting a new approach to defeating asthma by targeting the trigger -- the allergen -- before it can spark an attack. They describe their new compound, which they tested on rats, in ACS' Journal of Medicinal Chemistry.

Clive Robinson and colleagues explain that to prevent many health problems, the ideal approach to treatment or prevention involves getting to the cause of a condition and targeting it directly. Asthma, which occurs when the immune system goes into overdrive affecting the airway in response to an otherwise harmless substance, has posed a challenge to this model. That's because it can be set off by different allergens or irritants. But recent studies suggest that the picture might not be as complicated as previously thought. 

Scientists have found that dust mites are one of the most important triggers of allergic asthma. So Robinson's team wanted to find a way to neutralize mite allergens.

The researchers identified a compound that binds to a major dust mite allergen and turned it into an inhalable powder. They tested it on rats and found that it significantly dampened the animals' immune response when they were exposed to a variety of allergens. This compound and other similar inhibitors could hail a new direction in asthma treatment, say the researchers.

The authors acknowledge funding from the Wellcome Trust.

Source: American Chemical Society

Targeting fatty acids may be treatment strategy for arthritis, leukemia

The bone marrow of mice with normal ether lipid production (top) contains more white blood cells than are found in the bone marrow of mice with ether lipid deficiency (bottom).
Credit: Washington University School of Medicine

Enzymes linked to diabetes and obesity appear to play key roles in arthritis and leukemia, potentially opening up new avenues for treating these diverse diseases, according to new research at Washington University School of Medicine in St. Louis.

Working with genetically engineered mice, the researchers discovered that the same enzymes involved in turning carbohydrates into the building blocks of fats also influence the health of specialized white blood cells called neutrophils. Neutrophils are the most abundant type of white blood cell and a hallmark of inflammation, which is a key component of rheumatoid arthritis. Abnormally high levels of neutrophils also are common in patients with leukemia.

The study is published Jan. 6 in the journal Cell Metabolism.

"The link between these enzymes and neutrophils was a big surprise," said first author Irfan J. Lodhi, PhD, assistant professor of medicine. "We had never thought about treating rheumatoid arthritis or leukemia by targeting enzymes that produce fatty acids, but this work supports that line of thinking."

In the study, mice that couldn't make enzymes needed to produce a certain type of fat abruptly lost weight and developed extremely low white blood cell counts, with very few neutrophils. Without this fat, called an ether lipid, neutrophils died.

That discovery could lead to the targeting of ether lipids as a way to reduce the number of neutrophils in inflammatory diseases and leukemias. The researchers believe limiting, rather than eliminating, ether lipids may be the best approach because neutrophils are important infection fighters.

"This may be a pathway to limit inflammation," said senior investigator Clay F. Semenkovich, MD, the Herbert S. Gasser Professor of Medicine. "If we could reduce the activity of these enzymes without eliminating them entirely, it could lower the levels of ether lipids and potentially help patients with leukemia and inflammatory diseases such as arthritis."

Semenkovich, also a professor of cell biology and physiology and director of the Division of Endocrinology, Metabolism and Lipid Research, said the enzymes specifically target neutrophils without affecting other immune cells.

"So ether lipids appear to be a very precise target," he said.

Working with Daniel Link, MD, the Alan A. and Edith L. Wolff Distinguished Professor of Medicine, the researchers learned that inactivating the enzymes didn't harm the precursors of neutrophils; only mature neutrophils were killed.

That could mean strategies to limit the production of ether lipids might lower neutrophil levels only temporarily so that when treatment stops, a patient's neutrophil count gradually would rise, allowing the immune system to return to normal.

Source: Washington University in St. Louis

Computer model predicts red blood cell flow

Rendering of stream of blood cells. Credit: © Witold Krasowski / Fotolia

Adjacent to the walls of our arterioles, capillaries, and venules -- the blood vessels that make up our microcirculation -- there exists a peculiar thin layer of clear plasma, devoid of red blood cells. Although it is just a few millionths of a meter thick, that layer is vital. It controls, for example, the speed with which platelets can reach the site of a cut and start the clotting process.

"If you destroy this layer, your bleeding time can go way up, by 60 percent or more, which is a real issue in trauma," said Eric Shaqfeh, the Lester Levi Carter Professor and a professor of chemical engineering and mechanical engineering at Stanford University. Along with his colleagues, Shaqfeh has now created the first simplified computer model of the process that forms that layer -- a model that could help to improve the design of artificial platelets and medical treatments for trauma injuries and for blood disorders such as sickle cell anemia and malaria.

The model is described in a paper appearing in the journal Physics of Fluids.

The thin plasma layer, known as the Fåhræus-Lindqvist layer, is created naturally when blood flows through small vessels. In the microcirculation, the layer forms because red blood cells tend to naturally deform and lift away from the vessel walls. "The reason they don't just continually move away from the wall and go far away is because, as they move away, then also collide with other red blood cells, which force them back," Shaqfeh explained. "So the Fåhræus-Lindqvist layer represents a balance between this lift force and collisional forces that exist in the blood."

Because the deformation of red blood cells is a key factor in the Fåhræus-Lindqvist layer, its properties are altered in diseases, such as sickle cell anemia, that affect the shape and rigidity of those cells. The new model, which is a scaled-down version of an earlier numerical model by Shaqfeh and colleagues that provided the first large-scale, quantitative explanation of the formation of the layer, can predict how blood cells with varying shapes, sizes, and properties -- including the crescent-shaped cells that are the hallmark of sickle cell anemia -- will influence blood flow.

The model can also help predict the outcome of -- and perfect -- treatments for trauma-related injuries. One common thing to do during treatment for trauma injuries is to inject saline, which among other things reduces the hematocrit, the blood fraction of red blood cells. With our model, Shaqfeh said, "we can predict how thick the Fåhræus-Lindqvist layer will be with a given hematocrit, and therefore how close the platelets will be to the periphery of the blood vessels -- and how quickly clotting will occur.

Source: American Institute of Physics (AIP)

Nanotechnology against malaria parasites

After maturation, malaria parasites (yellow) are leaving an infected red blood cell and are efficiently blocked by nanomimics (blue). Credit: Fig: modified by University of Basel with permission from ACS

Malaria parasites invade human red blood cells, they then disrupt them and infect others. Researchers at the University of Basel and the Swiss Tropical and Public Health Institute have now developed so-called nanomimics of host cell membranes that trick the parasites. This could lead to novel treatment and vaccination strategies in the fight against malaria and other infectious diseases. Their research results have been published in the scientific journal ACS Nano.

For many infectious diseases no vaccine currently exists. In addition, resistance against currently used drugs is spreading rapidly. To fight these diseases, innovative strategies using new mechanisms of action are needed. The malaria parasite Plasmodium falciparum that is transmitted by the Anopheles mosquito is such an example. Malaria is still responsible for more than 600,000 deaths annually, especially affecting children in Africa (WHO, 2012).
Artificial bubbles with receptors

Malaria parasites normally invade human red blood cells in which they hide and reproduce. They then make the host cell burst and infect new cells. Using nanomimics, this cycle can now be effectively disrupted: The egressing parasites now bind to the nanomimics instead of the red blood cells.

Researchers of groups led by Prof. Wolfgang Meier, Prof. Cornelia Palivan (both at the University of Basel) and Prof. Hans-Peter Beck (Swiss TPH) have successfully designed and tested host cell nanomimics. For this, they developed a simple procedure to produce polymer vesicles -- small artificial bubbles -- with host cell receptors on the surface. The preparation of such polymer vesicles with water-soluble host receptors was done by using a mixture of two different block copolymers. In aqueous solution, the nanomimics spontaneously form by self-assembly.

Blocking parasites efficiently

Usually, the malaria parasites destroy their host cells after 48 hours and then infect new red blood cells. At this stage, they have to bind specific host cell receptors. Nanomimics are now able to bind the egressing parasites, thus blocking the invasion of new cells. The parasites are no longer able to invade host cells, however, they are fully accessible to the immune system.

The researchers examined the interaction of nanomimics with malaria parasites in detail by using fluorescence and electron microscopy. A large number of nanomimics were able to bind to the parasites and the reduction of infection through the nanomimics was 100-fold higher when compared to a soluble form of the host cell receptors. In other words: In order to block all parasites, a 100 times higher concentration of soluble host cell receptors is needed, than when the receptors are presented on the surface of nanomimics.

"Our results could lead to new alternative treatment and vaccines strategies in the future," says Adrian Najer first-author of the study. Since many other pathogens use the same host cell receptor for invasion, the nanomimics might also be used against other infectious diseases. The research project was funded by the Swiss National Science Foundation and the NCCR "Molecular Systems Engineering."

Source: University of Basel

Promising compound rapidly eliminates malaria parasite

A new report says that the rapid action of (+)-SJ733 will likely slow malaria drug resistance. Credit: Peter Barta, St. Jude Children's Research Hospital

An international research collaborative has determined that a promising anti-malarial compound tricks the immune system to rapidly destroy red blood cells infected with the malaria parasite but leave healthy cells unharmed. St. Jude Children's Research Hospital scientists led the study, which appears in the current online early edition of the Proceedings of the National Academy of Sciences (PNAS).

The compound, (+)-SJ733, was developed from a molecule identified in a previous St. Jude-led study that helped to jumpstart worldwide anti-malarial drug development efforts. Malaria is caused by a parasite spread through the bite of an infected mosquito. The disease remains a major health threat to more than half the world's population, particularly children. The World Health Organization estimates that in Africa a child dies of malaria every minute.

In this study, researchers determined that (+)-SJ733 uses a novel mechanism to kill the parasite by recruiting the immune system to eliminate malaria-infected red blood cells. In a mouse model of malaria, a single dose of (+)-SJ733 killed 80 percent of malaria parasites within 24 hours. After 48 hours the parasite was undetectable.

Planning has begun for safety trials of the compound in healthy adults.

Laboratory evidence suggests that the compound's speed and mode of action work together to slow and suppress development of drug-resistant parasites. Drug resistance has long undermined efforts to treat and block malaria transmission.

"Our goal is to develop an affordable, fast-acting combination therapy that cures malaria with a single dose," said corresponding author R. Kiplin Guy, Ph.D., chair of the St. Jude Department of Chemical Biology and Therapeutics. "These results indicate that SJ733 and other compounds that act in a similar fashion are highly attractive additions to the global malaria eradication campaign, which would mean so much for the world's children, who are central to the mission of St. Jude."

Whole genome sequencing of the Plasmodium falciparum, the deadliest of the malaria parasites, revealed that (+)-SJ733 disrupted activity of the ATP4 protein in the parasites. The protein functions as a pump that the parasites depend on to maintain the proper sodium balance by removing excess sodium.

The sequencing effort was led by co-author Joseph DeRisi, Ph.D., a Howard Hughes Medical Institute investigator and chair of the University of California, San Francisco Department of Biochemistry and Biophysics. Investigators used the laboratory technique to determine the makeup of the DNA molecule in different strains of the malaria parasite.

Researchers showed that inhibiting ATP4 triggered a series of changes in malaria-infected red blood cells that marked them for destruction by the immune system. The infected cells changed shape and shrank in size. They also became more rigid and exhibited other alterations typical of aging red blood cells. The immune system responded using the same mechanism the body relies on to rid itself of aging red blood cells.

Another promising class of antimalarial compounds triggered the same changes in red blood cells infected with the malaria parasite, researchers reported. The drugs, called spiroindolones, also target the ATP4 protein. The drugs include NITD246, which is already in clinical trials for treatment of malaria. Those trials involve investigators at other institutions.

"The data suggest that compounds targeting ATP4 induce physical changes in the infected red blood cells that allow the immune system or erythrocyte quality control mechanisms to recognize and rapidly eliminate infected cells," DeRisi said. "This rapid clearance response depends on the presence of both the parasite and the investigational drug. That is important because it leaves uninfected red blood cells, also known as erythrocytes, unharmed."

Laboratory evidence also suggests that the mechanism will slow and suppress development of drug-resistant strains of the parasite, researchers said.

Planning has begun to move (+)-SJ733 from the laboratory into the clinic beginning with a safety study of the drug in healthy adults. The drug development effort is being led by a consortium that includes scientists at St. Jude, the Swiss-based non-profit Medicines for Malaria Venture and Eisai Co., a Japanese pharmaceutical company.

Source: St. Jude Children's Research Hospital