We Could Solve Drug Resistance by Getting Microbes to Fight Each Other

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Scientists are in a battle to develop treatments faster than viruses develop barriers against them, but new research suggests putting pathogens at war with each other could be an effective way of countering existing drug resistance, as well as preventing it in the future.

In a study of mice infected with malaria, researchers combined traditional drug remedies with a manipulated version of a nutrient that the malaria parasites rely on.

Importantly, the resistant strain needed more of this particular nutrient than the drug-sensitive pathogen – so the pathogens that could ignore antibiotics ended up more hungry.

By restricting the nutrient supply, the team of researchers forced the drug-resistant parasites and the drug-sensitive parasites into competition with each other, eventually wiping out the infection.

“By taking advantage of competition between parasites inside a host, we managed to use an existing drug to successfully treat an infection, even when drug-resistant parasites were already there,” says biologist and lead researcher Nina Wale, now at the University of Michigan.

Drug resistance happens because pathogens, from bacteria to parasites, develop genetic mutations that shield them against treatment. Once that mutated pathogen survives, it can quickly replicate, rendering existing drugs ineffective.

Antibiotic resistance – when bacteria develop blockades against the power of antibiotics – is one specific and well-known type of drug resistance.

What happens in a typical scenario is that both drug-resistant and drug-sensitive variations of a pathogen initially thrive on the available resources. Traditional drugs work against the original strains, but the resistant mutations live on.

Take away those nutrients, and both drug-resistant and drug-sensitive variations suffer, the researchers found – they’re effectively fighting over scraps, and the drug-resistant ones need more scraps to survive.

The drugs take care of one pathogen strain, while the other naturally dies off.

warring pathogens 2(Penn State)

“In the absence of drug treatment, the only thing that stops resistant pathogens from spreading is competition with the pathogens that are sensitive to drug treatment,” says lead researcher Andrew Read, from Pennsylvania State University.

“We’re utilising the natural force of competition to control the resistant ones and using conventional drugs to treat the sensitive ones.”

When given the malaria nutrient in sufficient amounts, the infection persisted in 40 percent of the mice. The parasites also remained when mice were only given the drug-resistant strain of the disease to begin with.

But when the nutrient was limited, and both drug-resistant and drug-sensitive strains were used with the mice, the infection didn’t rebound in any of the animals. That was also the case even when the drug-resistant parasites were outnumbering the others.

Now the principle of competition has been shown to work, the next step is to develop treatments. Researchers have to identify specific nutrients that pathogens rely on, particularly the drug-resistant strains, and then work out exactly when to restrict those nutrients and by how much.

But if the method is effective in humans as well, the benefits will be worth it. Drug resistance is complicating attempts to treat HIV, tuberculosis, and malaria, responsible for millions of deaths worldwide each year.

Resistant pathogens also cause problems in patients recovering from major surgery and treatments like chemotherapy.

Ultimately the research could lead us towards new ways of fighting drug resistance, as well as extending the effective life of drugs that pathogens have already developed some protection against.

“Typically if a physician detects drug resistance in an infection, they won’t use that drug,” says Read. “And that’s okay if you’ve got another option.”

“But if you haven’t got another option, this is the sort of manipulation that would allow you to treat the patient even when resistance is there.”

The research has been published in PNAS.

The team also put together a video explaining the process, which you can see below:

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India and US soon to begin collaborative research on human immune phenotyping and infectious disease

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To foster, stimulate and expand research studies describing human immune phenotypes after vaccination or infection by supporting collaborative projects between Indian and US researchers, India and the US will soon begin collaborative research on human immune phenotyping and infectious diseases. However, HIV/AIDS research is excluded from this program.

The other major objective of this collaborative program is to characterize the diverse states of the human immune system prior to and following infection, prior to and following vaccination against an infectious disease, or prior to and following administration of an adjuvanted versus non-adjuvanted vaccine to assess the effects of the adjuvant.

This effort relies on the analysis of well-characterized human cohorts for immunophenotyping studies, which are defined as studies that apply a variety of systems biology approaches or other multi parameter phenotyping methods to discover and begin to define molecular signatures characteristic of the specific immune status induced by a particular infection or vaccine, or characteristic of the resting immune status in a particular population. The other goal of this Indo-US collaborative research, in collaboration with investigators of the NIAID Human Immunology Project Consortium (HIPC) is to generate research results leading to improved human vaccines and immunotherapeutics for infectious diseases.

This program is being conducted under the auspices of the Indo-US Vaccine Action Program (VAP) – a bilateral program of the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) within the Department of Health and Human Services, United States (US); and the Department of Biotechnology (DBT), Ministry of Science and Technology, Government of India; in conjunction with HIPC.

This collaborative effort is significant as in the broad scheme of global health, infectious diseases continue to plague various communities around the world, claiming numerous lives and significantly compromising the well-being of many others. Understanding basic immunological principles and the human immune response to various infectious agents, or to vaccines developed to prevent infectious diseases, can create knowledge to develop new vaccines, diagnostics and therapeutics. India, with its large and genetically diverse population, provides an opportunity to study human immunology in relation to a number of communicable diseases that are either uniquely tropical or global health threats. Moreover, preliminary epidemiological data generated by researchers in India suggest that the Indian population may have a wide variation of susceptibility or resistance to infectious pathogens due to diverse exposure conditions.

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(cenksns/Shutterstock) We Finally Know How Our Immune Cells Remember Diseases For So Long

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For many of us, remembering faces from 30 years ago can be something of a challenge. But cells in our immune system can remember old foes just fine, and we’ve never really been sure exactly how they manage it.

A new study has filled in missing details on the steps our body takes to remember pathogens, finally revealing the steps our immune cells take to preserve a reference library of past battles.

Scientists from the University of California, Berkeley, used a hydrogen isotope to label white blood cells inside volunteers, and tracked a specially selected virus from infection to immunity in order to record significant steps in the immune process.

The big picture of adaptive immunity and our ability to remember and eliminate specific pathogens has gradually built up over the past century.

We have different types of white blood cell that help spot and destroy invading cells. Two of these are B cells, which make and secrete antibodies to act as ‘name tags’ for the bad guys, and T cells, which perform a bunch of immune-related tasks such as recognising the foreign invaders.

Both include cell types that act as cellular historians, preserving remnants of past battles like old veterans.

Exactly how our immune cells do their job of identifying and then recording these events – at least on a chemical level – is where the story gets vague.

“This work addressed fundamental questions about the origin and longevity of human memory CD8+ T cells generated after an acute infection,” says senior author and nutritionist Marc Hellerstein from UC Berkeley.

Cytotoxic ‘CD8+’ T cells are a form of cellular assassin, raised in the body’s thymus to recognise familiar cells before being released to find unfamiliar fiends – such as cancer cells, bacteria, or cells infected with viruses.

On finding them, the body encourages these special T cells to proliferate. The small army releases chemicals into the enemy cells, punching holes in their membranes and destroying them.

Not all cytotoxic T cells go into battle to die glorious deaths taking down the enemy, though. Some stick around, and appear to be responsible for mounting quicker attacks should the tumours or pathogens return.

To get to the bottom of this process, the researchers gave 40 volunteers water that contained deuterium instead of standard hydrogen, which marked out any new cells they produced in their body at different intervals.

They then vaccinated them with an attenuated live yellow fever vaccine – a virus that the volunteers shouldn’t encounter in their home environment.

With the new CD8+ T cells readily identifiable, the researchers were able to track the cells over coming months to gain an idea of how their numbers and chemical make-up changed.

They discovered that after the initial response to the vaccination, a pool of memory cells forms. These cells look and behave more like naive cytotoxic T cells, with one difference; their genes are tagged epigenetically with the memories of war.

“These cells are like veteran soldiers, camped in the blood and tissues where they fight their battles, waiting for yellow fever to show up,” says Hellerstein.

“They are resting quietly and they wear the clothes of untested new recruits, but they are deeply experienced, ready to spring into action and primed to expand wildly and attack aggressively if invaders return.”

This quiescent state is the secret to their success, allowing them to quietly lurk in the background, ready to shift into high gear and attack the moment the pathogen returns.

On average, T cells have a half-life of about 30 days, meaning after a month most of the white cells have died. These disguised veteran T cells have a half-life of 450 days, meaning some of them can stick around for years, if not decades.

And the more we know about the memory system of our immune cells, the better we can use it to our advantage.

“Understanding the basis of effective long-term immune memory may help scientists develop better vaccines, understand differences among diseases and diagnose the quality of an individual person’s immune responses,” says Hellerstein.

This research was published in Nature.

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USFDA approves first drug for Eosinophilic Granulomatosis with Polyangiitis, a rare disease formerly known as the Churg-Strauss Syndrome

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The U.S. Food and Drug Administration today expanded the approved use of Nucala (mepolizumab) to treat adult patients with eosinophilic granulomatosis with polyangiitis (EGPA), a rare autoimmune disease that causes vasculitis, an inflammation in the wall of blood vessels of the body. This new indication provides the first FDA-approved therapy specifically to treat EGPA.

According to the National Institutes of Health, EGPA (formerly known as Churg-Strauss syndrome) is a condition characterized by asthma, high levels of eosinophils (a type of white blood cell that helps fight infection), and inflammation of small- to medium-sized blood vessels. The inflamed vessels can affect various organ systems including the lungs, gastrointestinal tract, skin, heart and nervous system. It is estimated that approximately 0.11 to 2.66 new cases per 1 million people are diagnosed each year, with an overall prevalence of 10.7 to 14 per 1,000,000 adults.

“Prior to today’s action, patients with this challenging, rare disease did not have an FDA-approved treatment option,” said Badrul Chowdhury, M.D., Ph.D., director of the Division of Pulmonary, Allergy, and Rheumatology Products in the FDA’s Center for Drug Evaluation and Research. “The expanded indication of Nucala meets a critical, unmet need for EGPA patients. It’s notable that patients taking Nucala in clinical trials reported a significant improvement in their symptoms.”

The FDA granted this application Priority Review and Orphan Drug designations. Orphan Drug designation provides incentives to assist and encourage the development of drugs for rare diseases.

Nucala was previously approved in 2015 to treat patients age 12 years and older with a specific subgroup of asthma (severe asthma with an eosinophilic phenotype) despite receiving their current asthma medicines. Nucala is an interleukin-5 antagonist monoclonal antibody (IgG1 kappa) produced by recombinant DNA technology in Chinese hamster ovary cells.

Nucala is administered once every four weeks by subcutaneous injection by a health care professional into the upper arm, thigh, or abdomen.

The safety and efficacy of Nucala was based on data from a 52-week treatment clinical trial that compared Nucala to placebo. Patients received 300 milligrams (mg) of Nucala or placebo administered subcutaneously once every four weeks while continuing their stable daily oral corticosteroids (OCS) therapy. Starting at week four, OCS was tapered during the treatment period. The primary efficacy assessment in the trial measured Nucala’s treatment impact on disease remission (i.e., becoming symptom free) while on an OCS dose less than or equal to 4 mg of prednisone. Patients receiving 300 mg of Nucala achieved a significantly greater accrued time in remission compared with placebo. A significantly higher proportion of patients receiving 300 mg of Nucala achieved remission at both week 36 and week 48 compared with placebo. In addition, significantly more patients who received 300 mg of Nucala achieved remission within the first 24 weeks and remained in remission for the remainder of the 52-week study treatment period compared with patients who received the placebo.

The most common adverse reactions associated with Nucala in clinical trials included headache, injection site reaction, back pain, and fatigue.

Nucala should not be administered to patients with a history of hypersensitivity to mepolizumab or one of its ingredients. It should not be used to treat acute bronchospasm or status asthmaticus. Hypersensitivity reactions, including anaphylaxis, angioedema, bronchospasm, hypotension, urticaria, rash, have occurred. Patients should discontinue treatment in the event of a hypersensitivity reaction. Patients should not discontinue systemic or inhaled corticosteroids abruptly upon beginning treatment with Nucala. Instead, patients should decrease corticosteroids gradually, if appropriate.

Health care providers should treat patients with pre-existing helminth infections before treating with Nucala because it is unknown if Nucala would affect patients’ responses against parasitic infections. In addition, herpes zoster infections have occurred in patients receiving Nucala. Health care providers should consider vaccination if medically appropriate.

The FDA granted approval of Nucala to GlaxoSmithKline.

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Our Sense of Smell Provides a New Way to Battle Spinal Cord Injuries

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Two Treatments Combined

Researchers from the University of Bristol have just shared the promising results of a new treatment for spinal cord injuries that could help regenerate nerves and potentially improve patients’ quality of life.

The new therapy involves the transplantation of cells that have been modified to secrete a molecule that helps to remove scarring caused by spinal cord damage. This scarring can limit the regrowth of nerves, thus greatly hindering a patient’s potential for recovery.

Previous studies have shown that the enzyme chondroitinase ABC (ChABC) is effective at promoting nerve regrowth when used as a part of drug therapies for spinal injuries. Unfortunately, the enzyme does not have a long life once injected. That means patients must be subjected to repeated treatments for the enzyme to be effective.

Olfactory ensheathing cells have the ability to regenerate and repair themselves over the course of a person’s life in order to maintain the sense of smell. That ability makes these cells ideal for genetic modification when the goal is prolonging a molecule’s lifespan.

This new treatment from the University of Bristol team utilizes this ability of the olfactory cells to prolong the secretion of ChABC for the treatment of spinal cord injuries.

For their study, which has been published in PLOS ONE, the researchers injected mice with canine olfactory ensheathing cells that had been genetically modified to secrete ChABC. After transplantation, they observed the successful secretion of ChABC as well as the removal of some scarring. They also noted signs of successful nerve regeneration.

It is an important proof-of-concept for this revolutionary treatment method, but more testing is needed to determine effectiveness.

“While these initial results look promising, in order to determine the longer-term survival of our genetically modified cells and assess functional recovery, such as recovery of walking or recovery of continence, we need to carry out further studies to test these cell transplants in more chronic injury models,” Liang-Fong Wong, Senior Lecturer at Bristol Medical School and part of the study’s team, said in a news release.

If future tests in mice go as hoped, the treatment can then be adapted for other animals and, eventually, humans.

Renewed Hope

An increasing number of potential treatments to help restore lost functionality after a spinal cord injury are in the works, and while many of these solutions hold great promise, more testing is needed to prove their efficacy and safety.

Still, scientific innovation in fields such as neuroscience, medicine, and even robotics is giving victims of spinal cord injuries renewed hope of recovery.

Researchers out of the University of Louisville’s Kentucky Spinal Cord Injury Research Center (KSCIRC) have recently restored voluntary movement in a 28-year-old patient who suffered a spinal cord injury from a motorcycle accident. His treatment combined new technology with established science — electric stimulation through an implant on the spine and traditional rehabilitation techniques — to deliver potentially life-changing results.

Meanwhile, a promising therapy from Rush University Medical Center was able to restore motor function in four out of six paralyzed patients. That cell therapy builds on decades of stem cell research, a promising area of study for spinal injury treatments.

Studies like these can be a great source of hope for both those living with spinal injuries and their loved ones. While it may be quite a long time before these treatments are proven to live up to their lofty promise, the goal of ending the ability of a single devastating moment to put mobility in a stranglehold is a fierce motivator.

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