Immunity boosting foods

New research explains why HIV is not cleared by the immune system

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Haitao GuoThis is a confocal fluorescence microscopy image of NLRX1 (green) in a HeLa cell (blue, nuclear stain).

Scientists at the University of North Carolina (UNC) School of Medicine and Sanford Burnham Prebys Medical Discovery Institute (SBP) have identified a human (host) protein that weakens the immune response to HIV and other viruses. The findings have important implications for improving HIV antiviral therapies, creating effective viral vaccines, and advance a new approach to treat cancer.

"Our study provides critical insight on a paramount issue in HIV research: Why is the body unable to mount an efficient immune response to HIV to prevent transmission?" said Sumit Chanda, Ph.D., professor and director of SBP's Immunity and Pathogenesis Program and co-senior author of the study. "This research shows that the host protein NLRX1 is responsible--it's required for HIV infection and works by repressing the innate immune response."

The innate immune response works by producing a cascade of signaling chemicals (interferons and cytokines) that trigger cytotoxic T cells to kill pathogens. Increasing evidence suggests that mounting an early, potent innate immune response is essential for the control of HIV infection, and may improve the effectiveness of vaccines.

"Importantly, we were able to show that deficiencies in NLRX1 reduce HIV replication, suggesting that the development of small molecules to modulate the innate immune response may inhibit viral transmission and promote immunity to infection," said Chanda. "We anticipate expanding our research to identify NLRX1 inhibitors."

How NLRX1 reduces innate immunity to HIV

Although HIV is a single-stranded RNA virus, after it infects an immune cell it's rapidly reverse transcribed into DNA, increasing the level of DNA found in the fluid portion of a cell (cytosol). Elevated cytosolic DNA triggers a sensor called STING (stimulator of interferon genes) that turns on the innate immune response.

"Until now, the mechanism by which NLRX1 promoted HIV infection was unexplored. We have shown that NLRX1 interacts directly with STING, essentially blocking its ability to interact with an enzyme called TANK-binding kinase 1 (TBK1)," said Haitao Guo, Ph.D., senior postdoctoral research associate in the laboratory of Jenny Ting, Ph.D., a University of North Carolina Lineberger Comprehensive Cancer Center member, the William R. Kenan Jr. Professor of Microbiology and Immunology at the UNC School of Medicine and lead author of the study. "The STING-TBK1 interaction is a critical step for interferon production in response to elevated cytosolic DNA, and initiates the innate immune response."

"This research expands our understanding of the role of host proteins in viral replication and the innate immune response to HIV infection, and can be extended to DNA viruses such as HSV and vaccinia," added Guo.

Relevance to cancer

"Our discovery that NLRX1 reduces the immune response to HIV is similar to the discovery of host immune checkpoints, such as PD-L1 and CTLA-1, that control the immune response to cancer," said Ting, co-senior author of the study.

Immune checkpoints are immunological "brakes" that prevent the over-activation of the immune system on healthy cells. Tumor cells often take advantage of these checkpoints to escape detection of the immune system. Several FDA-approved drugs that target checkpoints, called checkpoint inhibitors, are now available to treat certain cancers.

"Checkpoint inhibitors have made a huge impact on cancer treatment, and significant investment by the biotech/pharmaceutical sector is being made to identify STING inhibitors as the next generation of immune-oncology therapeutics," said Ting. "This study, showing that NLRX1 is a checkpoint of STING, sheds more light on the topic and will help advance those efforts."

Original publication:

Guo, Haitao et al.; "NLRX1 Sequesters STING to Negatively Regulate the Interferon Response, Thereby Facilitating the Replication of HIV-1 and DNA Viruses"; Cell Host & Microbe; 2016

Having worms can be good for the gut

THE WORM TURNS  Intestinal parasites may have an upside. Researchers have discovered that people with whipworms (Trichuris trichiura, left) and mice with Heligmosomoides polygyrus (right) have fewer inflammation-provoking bacteria than they do without the worms. 

Parasites trigger immune reaction that can calm inflammation

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TINA HESMAN SAEY

Parasitic worms may hold the secret to soothing inflamed bowels.

In studies of mice and people, parasitic worms shifted the balance of bacteria in the intestines and calmed inflammation, researchers report online April 14 in Science. Learning how worms manipulate microbes and the immune system may help scientists devise ways to do the same without infecting people with parasites.

Previous research has indicated that worm infections can influence people’s fertility (SN Online: 11/19/15), as well as their susceptibility to other parasite infections (SN: 10/5/13, p. 17) and to allergies (SN: 1/29/11, p. 26). Inflammatory bowel diseases also are less common in parts of the world where many people are infected with parasitic worms.

P’ng Loke, a parasite immunologist at New York University School of Medicine, and colleagues explored how worms might protect against Crohn’s disease. The team studied mice with mutations in the Nod2gene. Mutations in the human version of the gene are associated with Crohn’s in some people.

The mutant mice develop damage in their small intestines similar to that seen in some Crohn’s patients. Cells in the mice’s intestines don’t make much mucus, and more Bacteroides vulgatus bacteria grow in their intestines than in the guts of normal mice. Loke and colleagues previously discovered that having too much of that type of bacteria leads to inflammation that can damage the intestines.

In the new study, the researchers infected the mice with either a whipworm (Trichuris muris)or a corkscrew-shaped worm (Heligmosomoides polygyrus). Worm-infected mice made more mucus than uninfected mutant mice did. The parasitized mice also had less B. vulgatus and more bacteria from the Clostridiales family. Clostridiales bacteria may help protect against inflammation.

“Although we already knew that worms could alter the intestinal flora, they show that these types of changes can be very beneficial,” says Joel Weinstock, an immune parasitologist at Tufts University Medical Center in Boston.

Both the increased mucus and the shift in bacteria populations are due to what’s called the type 2 immune response, the researchers found. Worm infections trigger immune cells called T helper cells to release chemicals called interleukin-4 and interleukin-13. Those chemicals stimulate mucus production. The mucus then feeds the Clostridiales bacteria, allowing them to outcompete the Bacteroidales bacteria. It’s still unclear how the mucus encourages growth of one type of bacteria over another, Loke says.

Blocking interleukin-13 prevented the mucus production boost and the shift in bacteria mix, indicating that the worms work through the immune system. But giving interleukin-4 and interleukin-13 to uninfected mice could alter the mucus and bacterial balance without worms’ help, the researchers discovered.

Loke and colleagues also wanted to know if worms affect people’s gut microbes. So the researchers took fecal samples from people in Malaysia who were infected with parasitic worms.  

After taking a deworming drug, the people had less Clostridiales and more Bacteriodales bacteria than before. That shift in bacteria was associated with a drop in the number ofTrichuris trichiura whipworm eggs in the people’s feces, indicating that getting rid of worms may have negative consequences for some people.

Having data from humans is important because sometimes results in mice don’t hold up in people, says Aaron Blackwell, a human biologist at the University of California, Santa Barbara. “It’s nice to show that it’s consistent in humans.”

Worms probably do other things to limit inflammation as well, Weinstock says. If scientists can figure out what those things are, “studying these worms and how they do it may very well lead to the development of new drugs.” 

Gut reaction

In normal mice (top), the cells lining the intestines form fingers reaching toward the hollow center. In mice with a mutation in the Nod2 gene (middle), the intestinal lining is often swollen and damaged (an abscess shown). But infecting mutant mice with a whipworm (Trichuris muris) can restore the gut to health (bottom) by promoting mucus production and shifting the mix of bacteria that live the intestines.

Citations

D. Ramanan et al. Helminth infection promotes colonization resistance via type 2 immunity.Science. Published online April 14, 2016. doi: 10.1126/science.aaf3229. 

D. RAMANAN ET AL/SCIENCE 2016

Jimmy Carter is no longer being treated for cancer

Former President Jimmy Carter isno longer being treated for cancer.

In December 2015, Carterrevealed he had tested cancer freeonly a few months after initially sharing that he'd been diagnosed with metastatic (meaning it's spread from its primary spot) melanoma that had spread to his brain. Just a few months later, his doctors have let him know he no longer needs to be treated.

Carter, 91, had used a combination of radiation therapy and Keytruda, a relatively new kind of cancer drug, which was delivered intravenously once every three weeks.

For decades, doctors have treated patients using a combination of chemotherapy, radiation, and surgery to try to stifle the disease.

But in the past few years, doctors have started researching and using a promising tool: immunotherapy.

Unlike chemotherapy, which involves administering powerful drugs that kill both cancerous and healthy cells (most healthy cells can repair themselves), immunotherapies harness the power of the immune system to help it identify and knock out just the cancerous cells.

In cancer patients, a type of protein called PD-1 stops the immune system from doing its job and fighting the cancerous cells. Keytruda — the drug Carter used — gets in the way of those dysfunctional proteins, allowing the immune system to access the cancer cells. Then, with the help of the radiation therapy to shrink tumors, it can help knock out the cancer in some people.

The incredible success of the drug in Carter's case brought the treatment into the spotlight, but the therapy has been a long time coming.

More than a century in the works

Recent immunotherapy successes are far from the first time researchers have explored using the immune system to fight cancer.

As NPR noted, in the 1890s a doctor named William Coley treated his cancer patients by infecting them with bacteria. The treatment worked for some of them — with the immune system at full force to knock out the invading bacteria, the immune system could also take on the cancerous cells and kill them on the way, which wouldn't necessarily happen if the immune system wasn't stimulated.

At the time, very little was understood about the immune system, and after Coley died, his methods stopped being used in favor of radiation therapy. But in 1953, Coley's daughter, Helen Coley Nauts, founded the Cancer Research Institute, which works to understand the relationship between cancer and the immune system.

Streptococcus bacteria.

In the 1970s, scientists pursued an immunotherapy using a protein called tumor necrosis factor, or TNF, which the body makes in response to foreign organisms in the body, including bacteria and tumor cells.

Jan Vilcek, a microbiology professor at New York University and one of the scientists who worked on developing a TNF treatment at the time, told Business Insider that in animal testing, TNF was able to block the growth of tumors. But when put into humans, the added TNF was so toxic that it made people sick, even at doses that wouldn't kill tumors.

That was the end of immuno-oncology research for a while (though not the end of the story for TNF-related therapies).

Even so, the Cancer Research Institute stuck with it, and eventually in 2011, the first immunotherapy was approved in the US to treat melanoma. The drug, called Yervoy or ipilimumab, helps the immune system respond to cancerous cells by keeping it from pushing on the brakes before it has a chance to kill the cells. Since then, a number of other cancer treatments using the immune system have been approved, with more still in development.

"For us, the excitement that we're now seeing in the clinic is phenomenal," Cancer Research Institute CEO Jill O’Donnell-Tormey told Business Insider. "It's very validating for us."

Vilcek, too, is optimistic about the state of immunotherapies to treat cancer.

"I think it's really very very encouraging and in certain types of cancer, it's making a huge difference," Vilcek said.

In the middle of a cancer-treatment revolution

A woman is screened for skin cancer.

Immunotherapies are working incredibly well for some cancers, such as melanoma, lung cancer, head and neck cancer, and multiple myeloma.

Yet for others, there's still a lot to learn.

"We're a long way from knowing the full story," said O'Donnell-Tormey. For example, while Keytruda, the drug Carter used, has worked "dramatically well," it still doesn't have a success rate on its own that's anywhere close to 100% for the type of cancer it targets. "We need to understand why someone like Jimmy Carter is responding."

In fact, roughly 30% of metastatic melanoma patients using Keytruda alone respond completely. That's still better than the average response rate of chemotherapy treatments on their own in cases of metastatic melanoma. When the drug is combined with others, that success rate goes up, which also holds true for other medications like chemotherapy. But for those who still don't respond at all, that's the challenge. And combining different medications and therapies might be the answer.

This year was a good one for immunotherapies: In October 2015, Keytruda was also approvedto treat a form of lung cancer. It moved forward in getting developed to treat a wide variety of other cancer types as well.

In the last year, Opdivo, another drug that targets the PD-1 protein like Keytruda and was originally approved to treat patients with certain types of melanoma, was also approved to treat forms of lung cancer and kidney cancer.

In blood-cancer treatment, 2015 saw the approvals of more than one multiple-myeloma immunotherapy. Others went so far as to get approval for a genetically modified herpes virus that's programmed to kill tumor cells in patients with melanoma that recurs after surgery (making history as the first cancer viral therapy).

And investors expect new cancer immunotherapies to make billions of dollars in sales in the next couple of years.

• Lydia Ramsey

SOME VIRUSES HAVE THEIR OWN IMMUNE SYSTEMS

Mimivirus

A large virus, called a mimivirus, under an electron microscope.

AND IT WORKS KIND OF LIKE CRISPR

By Alexandra Ossola

Just like bacteria, giant viruses need to protect themselves from invasive microbes, and they do so with the help of an immune system that works quite similar to the CRISPR system found in bacteria (and now borrowed by human geneticists) according to a study published today in Nature.

In 2003, researchers Didier Raoult and Bernard La Scola of Aix-Marseille University in France discovered something strange lurking in amoebas: giant viruses, visible under a typical microscope, and about four times larger than the ones we often see infecting human cells. Collectively they’re called mimiviruses because they appear to mimic bacteria.

In the intervening years, these researchers have discovered 150 different types of these large viruses, according to Stat News, such as megaviruses andpandoraviruses. Many of these challenge the traditional definition of a virus; Raoult has controversially claimed that mimiviruses make up a new branch of the tree of life, according to Nature News.

One way these mimiviruses have proven different is that they themselves can be attacked by smaller viruses. But in 2014, the researchers realized that viruses can invade only certain types of mimiviruses. They hypothesized that these large viruses had immune systems much like bacteria's, in which they would incorporate little bits of their attackers’ DNA into their own genetic code. That way, if the same virus tried to invade again, the host would be able to identify the unwanted attacker and kill it. Those bits of invaders’ genetic code in an organism’s DNA are called CRISPR; by taking advantage of this unique pattern and of its accompanying gene-snipping enzyme, Cas9, researchers have been working to create more robust crops and eliminatediseases in humans.

The researchers wanted to test these large viruses to see if they did in fact have a CRISPR-like immune system. So they analyzed the genomes of 60 strains of mimiviruses looking for the telltale snips of DNA from a much smaller virus (or virophage) called Zamilon, known to attack many of them. As they expected, the researchers found that mimiviruses immune to Zamilon had bits of its genetic code lodged in their own. The researchers also found that the mimiviruses contain enzymes capable of degrading foreign DNA, just as CRISPR does. The researchers named this viral immune system the MIMIVIRE, which stands for “mimivirus virophage resistance element.”

As The Atlantic points out, the MIMIVIRE isn’t the same as CRISPR—it’s just a good example of convergent evolution. But it does provide more evidence that mimiviruses are different from other, simpler viruses, possibly shifting the discussion about their evolutionary origins or whether they’re alive. In the future, the researchers hope to better understand the mechanisms that drive the MIMIVIRE.

Blood Test Can Detect Every Virus You’ve Ever Had

By Kiona Smith-Strickland

Viral infections come and go countless times over our lives. Some, like mononucleosis, might knock you flat for weeks, while others never produce any symptoms at all. And some may impact your immune system in subtle ways for years after the infection.

Soon, it could be possible to get a full history of every viral infection you’ve ever had, using just a drop of blood. Researchers have developed a blood test that detects the remnants of more than 1,000 strains of 206 virus species. The test could someday help doctors diagnose current ailments and reveal more about how viruses impact our long-term health.

A Viral Time Machine

When you’re exposed to a virus, your body’s immune system creates new B cells tailored to fight that virus. Immune memory last for several years, and sometimes even decades, after exposure, so the antibodies in your blood can act like fingerprints of every virus that’s ever been in your body.

Currently, if doctors think you might have a viral infection, they test your blood for antibodies to that virus. Today’s blood tests can only test for a single virus at a time, and doctors have to know which virus they’re looking for, so they can look for a specific set of antibodies.

Now, researchers at the Howard Hughes Medical Institute say that their new technique, which they’ve dubbed VirScan, will allow doctors to scan a patient’s blood for antibodies to every known human virus at the same time. “This means that you can look at viral exposures in an unbiased way without having to suspect a particular infection ahead of time,” researcher Tomasz Kula told Discover. “Our approach could be useful for patients with undiagnosed diseases where it is unclear which viruses to test for.”

How It Works

To build VirScan, lead author George J. Xu and his team essentially created a library of mock viruses. They used a common bacteria-eating virus called a bacteriophage as their starting material. Then they added DNA for external proteins called peptides to make the viruses look, to the immune system, like one of over 1,000 different human viruses.

When the researchers put the mock viruses into a drop of blood, the antibodies in that person’s blood would bind to the peptide of whichever virus he or she had previously been exposed to, either through infection or vaccination.

Xu and his colleagues tested VirScan on a group of 569 volunteers from Peru, South Africa, Thailand, and the U.S. Most people had antibodies in their blood for about ten different viruses, but some people had dozens. Two members of the study had antibodies to 84 different viruses, the researchersreport today in Science.

History in a Drop of Blood

In addition to diagnostics, VirScan could also help researchers understand the connection between viral infection and diseases, such as type 1 diabetes, asthma, and irritable bowel syndrome. The causes of these ailments aren’t completely understood but researchers believe they are linked to past infections. “We can look comprehensively for viral exposures that correlate with these kinds of diseases in a way that would be infeasible if you had to test for each virus separately,” said Kula. “We hope that VirScan can be used to generate new hypotheses about what role specific viral infections may play in complex diseases.”

And the test could tell scientists more about the basic workings of the immune system. For instance, although any virus may have multiple peptides on its surface, the researchers found that most people who had been exposed to a particular virus had antibodies for one specific peptide. “We think that this may tell us something fundamental about the human immune system, and it also provides valuable information for developing new diagnostics,” said Kula.

Refining the Process

Xu and his colleagues are still working to refine VirScan, but they ultimately hope to make it available for clinical use.

“From a personal health standpoint, you could imagine an annual blood test for all viral exposures to try to find infections before they cause symptoms. For example, many people are not aware that they are infected with Hepatitis C virus, which can cause liver damage and cancer. Often, this is because patients do not show symptoms for many years and so they did not get tested for this particular virus,” said Kula.

The researchers say that VirScan’s method could also be applied to look for infection history of other types of pathogens, such as bacteria, fungi, and parasites.