It’s fair to say parasites are generally bad for their hosts. Many cause disease and death so, like most species, we humans usually try to avoid infection at all costs.
But it turns out that some parasites, although potentially harmful in isolation, can in fact help hosts to cope with more deadly infections.
Understanding when parasitism is beneficial has important implications for how we manage infectious diseases, but we currently know very little about this phenomenon.
Our new study, published in Evolution Letters, tells us that parasites can readily evolve different mechanisms to defend their hosts from other infections, which suggests that host protection should be common in nature.
The idea that “the enemy of my enemy is my friend” has been around in human society for a long time but it is far from unique to human conflict. The natural world is full of examples where parasites are harmful under some conditions and helpful under others.
Similarly, bacteria that commonly infect insects are usually costly but can provide protection against more deadly infections.
And the larvae of monarch butterflies are more likely to survive infection by a parasitic fly when they are also infected by a protozoan (single-celled organism).
Parasites can also help their hosts in other ways, for example by causing more serious disease in other species. This is one of the main reasons why grey squirrels have rapidly displaced red squirrels from most of the UK.
Grey squirrels are carriers of squirrel pox virus, which is usually fatal to red squirrels but is rarely harmful to greys. Likewise, some species of bacteria engage in a form of primitive biological warfare by carrying viruses to which competing bacteria are not immune.
These examples reveal that being infected is not necessarily a bad thing and in fact can sometimes be beneficial. But what they don’t tell us is how and when parasites evolve to be useful to their hosts.
Recent lab experiments have shown that mildly harmful bacteria living inside microscopic worms can evolve in just a few days to protect their hosts from a lethal infection.
This striking result indicates that bacteria can rapidly evolve host protection against other infectious diseases.
Still, very little is known about how and when such evolution occurs in nature. And if a parasite evolves to protect its host from a more deadly infection, has the enemy now become a friend?
From foe to friend
Using mathematical modelling, we explored the evolution of two forms of host protection: resistance and tolerance.
Parasites that protect by conferring resistance to their hosts reduce the likelihood that a second species will be able to infect them, such as when bacteria in the gut prevent colonisation by other microbes.
In contrast, parasites that confer tolerance to their hosts reduce the harm caused by another species after it infects them, as appears to be the case with the protozoa that protect monarch butterfly larvae from parasitic flies.
We discovered that both forms of host protection evolve under a wide range of conditions even though the protective parasite may have to divert resources from its own growth or reproduction to defend the host.
Protection still evolves because this cost is more than offset by the increased survival of the host (and hence the protective parasite).
But there are some notable differences between the two forms of protection. For instance, resistance usually increases the population size of the host, but tolerance can have a negative effect because it increases the overall prevalence of disease.
These differences indicate that the mechanism of protection is crucial for determining whether a protective parasite is truly beneficial.
Does the host evolve to harbour the protective parasite, and is this how we developed a symbiotic relationship with some of our gut bacteria? Can more harmful parasites evolve to overcome host protection?
Answering questions like these can help us find new ways to treat infectious diseases.
The results of our research shed light on a fascinating biological phenomenon about which we still know very little.
Yet taken together with the growing number of examples of host protection, it is clear – at least if you’re hosting a parasite – that the enemy of your enemy can indeed be your friend.
The U.S. Food and Drug Administration issued a historic action making the first gene therapy available in the United States, ushering in a new approach to the treatment of cancer and other serious and life-threatening diseases.
The FDA approved Kymriah (tisagenlecleucel) for certain pediatric and young adult patients with a form of acute lymphoblastic leukemia (ALL).
“We’re entering a new frontier in medical innovation with the ability to reprogram a patient’s own cells to attack a deadly cancer,” said FDA Commissioner Scott Gottlieb, M.D. “New technologies such as gene and cell therapies hold out the potential to transform medicine and create an inflection point in our ability to treat and even cure many intractable illnesses. At the FDA, we’re committed to helping expedite the development and review of groundbreaking treatments that have the potential to be life-saving.”
Kymriah, a cell-based gene therapy, is approved in the United States for the treatment of patients up to 25 years of age with B-cell precursor ALL that is refractory or in second or later relapse.
Kymriah is a genetically-modified autologous T-cell immunotherapy. Each dose of Kymriah is a customized treatment created using an individual patient’s own T-cells, a type of white blood cell known as a lymphocyte. The patient’s T-cells are collected and sent to a manufacturing center where they are genetically modified to include a new gene that contains a specific protein (a chimeric antigen receptor or CAR) that directs the T-cells to target and kill leukemia cells that have a specific antigen (CD19) on the surface. Once the cells are modified, they are infused back into the patient to kill the cancer cells.
ALL is a cancer of the bone marrow and blood, in which the body makes abnormal lymphocytes. The disease progresses quickly and is the most common childhood cancer in the U.S. The National Cancer Institute estimates that approximately 3,100 patients aged 20 and younger are diagnosed with ALL each year. ALL can be of either T- or B-cell origin, with B-cell the most common. Kymriah is approved for use in pediatric and young adult patients with B-cell ALL and is intended for patients whose cancer has not responded to or has returned after initial treatment, which occurs in an estimated 15-20 percent of patients.
“Kymriah is a first-of-its-kind treatment approach that fills an important unmet need for children and young adults with this serious disease,” said Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research (CBER). “Not only does Kymriah provide these patients with a new treatment option where very limited options existed, but a treatment option that has shown promising remission and survival rates in clinical trials.”
The safety and efficacy of Kymriah were demonstrated in one multicenter clinical trial of 63 pediatric and young adult patients with relapsed or refractory B-cell precursor ALL. The overall remission rate within three months of treatment was 83 percent.
Treatment with Kymriah has the potential to cause severe side effects. It carries a boxed warning for cytokine release syndrome (CRS), which is a systemic response to the activation and proliferation of CAR T-cells causing high fever and flu-like symptoms, and for neurological events. Both CRS and neurological events can be life-threatening. Other severe side effects of Kymriah include serious infections, low blood pressure (hypotension), acute kidney injury, fever, and decreased oxygen (hypoxia). Most symptoms appear within one to 22 days following infusion of Kymriah. Since the CD19 antigen is also present on normal B-cells, and Kymriah will also destroy those normal B cells that produce antibodies, there may be an increased risk of infections for a prolonged period of time.
The FDA today also expanded the approval of Actemra (tocilizumab) to treat CAR T-cell-induced severe or life-threatening CRS in patients 2 years of age or older. In clinical trials in patients treated with CAR-T cells, 69 percent of patients had complete resolution of CRS within two weeks following one or two doses of Actemra.
Because of the risk of CRS and neurological events, Kymriah is being approved with a risk evaluation and mitigation strategy (REMS), which includes elements to assure safe use (ETASU). The FDA is requiring that hospitals and their associated clinics that dispense Kymriah be specially certified. As part of that certification, staff involved in the prescribing, dispensing, or administering of Kymriah are required to be trained to recognize and manage CRS and neurological events. Additionally, the certified health care settings are required to have protocols in place to ensure that Kymriah is only given to patients after verifying that tocilizumab is available for immediate administration. The REMS program specifies that patients be informed of the signs and symptoms of CRS and neurological toxicities following infusion – and of the importance of promptly returning to the treatment site if they develop fever or other adverse reactions after receiving treatment with Kymriah.
To further evaluate the long-term safety, Novartis is also required to conduct a post-marketing observational study involving patients treated with Kymriah.
The FDA granted Kymriah Priority Review and Breakthrough Therapy designations. The Kymriah application was reviewed using a coordinated, cross-agency approach. The clinical review was coordinated by the FDA’s Oncology Center of Excellence, while CBER conducted all other aspects of review and made the final product approval determination.
The FDA granted approval of Kymriah to Novartis Pharmaceuticals Corp. The FDA granted the expanded approval of Actemra to Genentech Inc.
Up until now, it’s only been possible to track where cells are in their life cycle once they’re dead. However, a new study outlines a method of analysing living cells by taking a close look at their nucleus.
The new study by researchers at New York University (NYU), as published in the journal Proceedings of the National Academy of Sciences (PNAS), has established a method of gauging what stage of the cell cycle a living cell is currently at.
Previously, it was only possible to take such measurements when working with a dead cell.
It was already known that the size and shape of a cell nucleus typically undergo big changes over the course of a cell’s lifespan.
However, the challenge of taking measurements from a living cell meant that we didn’t know whether its shape changed over a shorter span of time.
Using a cutting-edge fluorescence microscope, researchers were able to observe a previously undetected flicker of the nuclear envelope, which takes place over the course of just a few seconds. The amplitude of this fluctuation was seen to decrease as the cell cycle went on.
This motion could serve as an internal clock, as scientists could take measurements in order to understand what point in the cell cycle a living cell is currently occupying.
Being able to discern where a cell sits in its life cycle will hopefully facilitate a greater understanding of the most basic processes of human biology. This discovery stands to improve our knowledge of both healthy and diseased cells.
“We know that structural and functional errors of the nuclear envelope lead to a large number of developmental and inherited disorders, such as cardiomyopathy, muscular dystrophy, and cancer,” Alexandra Zidovska, the paper’s senior author and an assistant professor of physics at NYU, said in a statement released by the school.
“Illuminating the mechanics of nuclear shape fluctuations might contribute to efforts to understand the nuclear envelope in health and disease.”
The U.S. Food and Drug Administration approved Mylotarg (gemtuzumab ozogamicin) for the treatment of adults with newly diagnosed acute myeloid leukemia whose tumors express the CD33 antigen (CD33-positive AML). The FDA also approved Mylotarg for the treatment of patients aged 2 years and older with CD33-positive AML who have experienced a relapse or who have not responded to initial treatment (refractory).
Mylotarg originally received accelerated approval in May 2000 as a stand-alone treatment for older patients with CD33-positive AML who had experienced a relapse. Mylotarg was voluntarily withdrawn from the market after subsequent confirmatory trials failed to verify clinical benefit and demonstrated safety concerns, including a high number of early deaths. Today’s approval includes a lower recommended dose, a different schedule in combination with chemotherapy or on its own, and a new patient population.
“We are approving Mylotarg after a careful review of the new dosing regimen, which has shown that the benefits of this treatment outweigh the risk,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Mylotarg’s history underscores the importance of examining alternative dosing, scheduling, and administration of therapies for patients with cancer, especially in those who may be most vulnerable to the side effects of treatment.”
AML is a rapidly progressing cancer that forms in the bone marrow and results in an increased number of white blood cells in the bloodstream. The National Cancer Institute of the National Institutes of Health estimates that approximately 21,380 people will be diagnosed with AML this year and that 10,590 patients with AML will die of the disease.
Mylotarg is a targeted therapy that consists of an antibody connected to an anti-tumor agent that is toxic to cells. It is thought to work by taking the anti-tumor agent to the AML cells that express the CD33 antigen, blocking the growth of cancerous cells and causing cell death.
The safety and efficacy of Mylotarg in combination with chemotherapy for adults were studied in a trial of 271 patients with newly diagnosed CD33-positive AML who were randomized to receive Mylotarg in combination with daunorubicin and cytarabine or to receive daunorubicin and cytarabine without Mylotarg. The trial measured “event-free survival,” or how long patients went without certain complications, including failure to respond to treatment, disease relapse or death, from the date they started the trial. Patients who received Mylotarg in combination with chemotherapy went longer without complications than those who received chemotherapy alone (median, event-free survival 17.3 months vs. 9.5 months).
The safety and efficacy of Mylotarg as a stand-alone treatment were studied in two, separate trials. The first trial included 237 patients with newly diagnosed AML who could not tolerate or chose not to receive intensive chemotherapy. Patients were randomized to receive treatment with Mylotarg or best supportive care. The trial measured “overall survival,” or how long patients survived from the date they started the trial. Patients who received Mylotarg survived longer than those who received only best supportive care (median overall survival 4.9 months vs. 3.6 months). The second trial was a single-arm study that included 57 patients with CD33-positive AML who had experienced one relapse of disease. Patients received a single course of Mylotarg. The trial measured how many patients achieved a complete remission. Following treatment with Mylotarg, 26 percent of patients achieved a complete remission that lasted a median 11.6 months.
Common side effects of Mylotarg include fever (pyrexia), nausea, infection, vomiting, bleeding, low levels of platelets in the blood (thrombocytopenia), swelling and sores in the mouth (stomatitis), constipation, rash, headache, elevated liver function tests, and low levels of certain white blood cells (neutropenia). Severe side effects of Mylotarg include low blood counts, infections, liver damage, blockage of the veins in the liver (hepatic veno-occlusive disease), infusion-related reactions, and severe bleeding (hemorrhage). Women who are pregnant or breastfeeding should not take Mylotarg, because it may cause harm to a developing fetus or a newborn baby. Patients with hypersensitivity to Mylotarg or any component of its formulation should not use Mylotarg.
The prescribing information for Mylotarg includes a boxed warning that severe or fatal liver damage (hepatotoxicity), including blockage of veins in the liver (veno-occlusive disease or sinusoidal obstruction syndrome), occurred in some patients who took Mylotarg.
Mylotarg received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.
The FDA granted the approval of Mylotarg to Pfizer Inc.
The role played by the millions of bacteria that live in our intestines is poorly understood, but the more we learn, the more complex it gets.
And, according to two new studies out this week, this microbiome could play a more significant part in multiple sclerosis than we thought.
Multiple sclerosis, which affects 2.5 million people around the world, is thought to be an autoimmune disease. During a relapse, or attack, immune cells breach the blood-brain barrier and enter the central nervous system, something that is highly restricted in healthy people.
These immune cells then attack the protective coating around nerve cells. This causes inflammation in the brain, which in turn causes scarring. These scars are responsible for the physical symptoms of MS.
No one knows what causes it, but a growing body of research is connecting it to the gut microbiome.
Several previous studies have identified microbiome differences between MS patients and healthy people, but new studies by teams at the University of California, San Francisco and the Max Planck Institute of Neurobiology in Germany have identified how the different gut microbiome may play a role.
In the University of California study, led by geneticist Sergio Baranzini, two genera of bacteria, Acinetobacter and Akkermansia, were found to be four times more abundant in MS patients than healthy people.
They also showed that a genus of bacterium called Parabacteroides is four times more abundant in healthy people than MS patients.
Baranzini’s team wasn’t simply trying to identify microbiome differences. They were trying to see what those differences mean. So they put a type of immune cell that transforms based on the threat it encounters in contact with Acinetobacter and Akkermansia.
These cells transformed into a type of T helper cells, which trigger inflammation as a mechanism for fighting infection. Moreover, Acinetobacter slowed the production of regulatory T cells, which suppress the immune response.
These regulatory T cells are very helpful for autoimmune patients, so limiting their production while accelerating production of cells that cause inflammation could exacerbate relapses.
To observe this, they transferred the bacteria to healthy mice and induced brain inflammation. Within 20 days, the mice had developed severe brain inflammation, compared to mice who had had gut bacteria transferred from healthy people. These control mice “didn’t get nearly as sick,” Baranzini said.
The second study, led by Gurumoorthy Krishnamoorthy and Hartmut Wekerle, looked at 34 sets of identical twins between the ages of 21 and 63, where only one twin had developed MS.
Again, they found that Akkermansia was more abundant in the twins with MS.
The took the microbiome from each of the 68 twins and transplanted them into mice predisposed to develop an autoimmune disease similar to MS.
After 12 weeks, they found mice transplanted with the MS twins’ microbiome were three times more likely to develop a brain inflammation than those who were transplanted with the healthy microbiome.
Both studies had small sample sizes, and, Baranzini notes, it’s too early to be thinking about potential treatments based on the information. However, both studies demonstrate that there is more to be learned from studying the microbiome in relation to multiple sclerosis.
“Our results,” the University of California researchers wrote in their paper, “expand the knowledge of the microbial regulation of immunity and may provide a basis for the development of microbiome-based therapeutics in autoimmune diseases.”