Category: Immunology

Duke’s Fundamental Research Can Turn Viruses Into Marvels

On April 14, 2020

In Biomedical Engineering, Cancer, Faculty, Genetics/Genomics, Global Health, Immunology, Medicine

The COVID-19 epidemic has impacted the Duke research enterprise in profound ways. Nearly all laboratory-based research has been temporarily halted, except for research directly connected to the fight against COVID-19. It will take much time to return to normal, and that process of renewal will be gradual and will be implemented carefully.

Trying to put this situation into a broader perspective, I thought of the 1939 essay by Abraham Flexner published in Harper’s magazine, entitled “The Usefulness of Useless Knowledge.” Flexner was the founding Director of the Institute for Advanced Study at Princeton, and in that essay, he ruminated on much of the type of knowledge acquired at research universities — knowledge motivated by no objective other than the basic human desire to understand. As Flexner said, the pursuit of this type of knowledge sometimes leads to surprises that transform the way we see that which was previously taken for granted, or for which we had previously given up hope. Such knowledge is sometimes very useful, in highly unintended ways.

The 1918 influenza pandemic led to 500 million confirmed cases, and 50 million deaths. In the Century since, consider how far we have come in our understanding of epidemics, and how that knowledge has impacted our ability to respond. People like Greg Gray, a professor of medicine and member of the Duke Global Health Institute (DGHI), have been quietly studying viruses for many years, including how viruses at domestic animal farms and food markets can leap from animals to humans. Many believe the COVID-19 virus started from a bat and was transferred to a human. Dr. Gray has been a global leader in studying this mechanism of a potential viral pandemic, doing much of his work in Asia, and that experience makes him uniquely positioned to provide understanding of our current predicament.

From the health-policy perspective, Mark McClellan, Director of the Duke Margolis Center for Health Policy, has been a leading voice in understanding viruses and the best policy responses to an epidemic. As a former FDA director, he has experience bringing policy to life, and his voice carries weight in the halls of Washington. Drawing on faculty from across Duke and its extensive applied policy research capacity, the Margolis Center has been at the forefront in guiding policymakers in responding to COVID-19.

Through knowledge accrued by academic leaders like Drs. Gray and McClellan, one notes with awe the difference in how the world has responded to a viral threat today, relative to 100 years ago. While there has been significant turmoil in many people’s lives today, as well as significant hardship, the number of global deaths caused by COVID-19 has been reduced substantially relative to 1918.

One of the seemingly unusual aspects of COVID-19 is that a substantial fraction of the population infected by the virus has no symptoms. However, those asymptomatic individuals shed the virus and infect others. While most people have no or mild symptoms, other people have very adverse effects to COVID-19, some dying quickly.

This heterogeneous response to COVID-19 is a characteristic of viruses studied by Chris Woods, a professor medicine in infectious diseases. Dr. Woods, and his colleagues in the Schools of Medicine and Engineering, have investigated this phenomenon for years, long before the current crisis, focusing their studies on the genomic response of the human host to a virus. This knowledge of viruses has made Dr. Woods and his colleagues leading voices in understanding COVID-19, and guiding the clinical response.

A team led by Greg Sempowski, a professor of pathology in the Human Vaccine Institute is working to isolate protective antibodies from SARS-CoV-2-infected individuals to see if they may be used as drugs to prevent or treat COVID-19. They’re seeking antibodies that can neutralize or kill the virus, which are called neutralizing antibodies.

Many believe that only a vaccine for COVID-19 can truly return life to normal. Human Vaccine Institute Director Barton Haynes, and his colleagues are at the forefront of developing that vaccine to provide human resistance to COVID-19. Dr. Haynes has been focusing on vaccine research for numerous years, and now that work is at the forefront in the fight against COVID-19.

Engineering and materials science have also advanced significantly since 1918. Ken Gall, a professor of mechanical engineering and materials science has led Duke’s novel application of 3D printing to develop methods for creatively designing personal protective equipment (PPE). These PPE are being used in the Duke hospital, and throughout the world to protect healthcare providers in the fight against COVID-19.

Much of the work discussed above, in addition to being motivated by the desire to understand and adapt to viruses, is motivated from the perspective that viruses must be fought to extend human life.

In contrast, several years ago Jennifer Doudna and Emmanuelle Charpentier, academics at Berkeley and the Max Planck Institute, respectively, asked a seemingly useless question. They wanted to understand how bacteria defended themselves against a virus. What may have made this work seem even more useless is that the specific class of viruses (called phage) that infect bacteria do not cause human disease. Useless stuff! The kind of work that can only take place at a university. That basic research led to the discovery of clustered regularly interspaced short palindromic repeats (CRISPR), a bacterial defense system against viruses, as a tool for manipulating genome sequences. Unexpectedly, CRISPR manifested an almost unbelievable ability to edit the genome, with the potential to cure previously incurable genetic diseases.

Charles Gersbach, a professor of Biomedical Engineering, and his colleagues at Duke are at the forefront of CRISPR research for gene and cell therapy. In fact, he is working with Duke surgery professor and gene therapy expert Aravind Asokan to engineer another class of viruses, recently approved by the FDA for other gene therapies, to deliver CRISPR to diseased tissues. Far from a killer, the modified virus is essential to getting CRISPR to the right tissues to perform gene editing in a manner that was previously thought impossible. There is hope that CRISPR technology can lead to cures for sickle cell and other genetic blood disorders. It is also being used to fight cancer and muscular dystrophy, among many other diseases and it is being used at Duke by Dr. Gersbach in the fight against COVID-19.

In another seemingly bizarre use of a virus, a modified form of the polio virus is being used at Duke to fight glioblastoma, a brain tumor. That work is being pursued within the Preston Robert Tisch Brain Tumor Center, for which David Ashley is the Director. The use of modified polio virus excites the innate human immune system to fight glioblastoma, and extends life in ways that were previously unimaginable. But there are still many basic-science questions that must be overcome. The remarkable extension of life with polio-based immunotherapy occurs for only 20% of glioblastoma patients. Why? Recall from the work of Dr. Woods discussed above, and from our own observation of COVID-19, not all people respond to viruses in the same way. Could this explain the mixed effectiveness of immunotherapy for glioblastoma? It is not known at this time, although Dr. Ashley feels it is likely to be a key factor. Much research is required, to better understand the diversity in the host response to viruses, and to further improve immunotherapy.

The COVID-19 pandemic is a challenge that is disrupting all aspects of life. Through fundamental research being done at Duke, our understanding of such a pandemic has advanced markedly, speeding and improving our capacity to respond. By innovative partnerships between Duke engineers and clinicians, novel methods are being developed to protect frontline medical professionals. Further, via innovative technologies like CRISPR and immunotherapy — that could only seem like science fiction in 1918 (and as recently as 2010!) — viruses are being used to save lives for previously intractable diseases.

Viruses can be killers, but they are also scientific marvels. This is the promise of fundamental research; this is the impact of Duke research.

“We shall not cease from exploration
And the end of all our exploring
Will be to arrive where we started
And know the place for the first time.”

T.S. Eliot, Four Quartets

Post by Lawrence Carin, Vice President for Research

#UniqueScientists Is Challenging Stereotypes About Who Becomes a Scientist

By Irene Park

On February 24, 2020

In Behavior/Psychology, Biology, Immunology, Science Communication & Education

University of North Carolina cell biologist Efra Rivera-Serrano says he doesn’t look like a stereotypical scientist: he’s gay, Puerto Rican, and a personal trainer.

Known on Twitter as @NakedCapsid or “the guy who looks totally buff & posts microscopy threads,” he tweets about virology and cell biology and aims to make science more accessible to the non-science public.

But science communication encompasses more than posting the facts of viral transmission or sending virtual valentines featuring virus-infected cells, Rivera-Serrano says. As a science communicator, he’s also committed to conveying truths that are even more rarely expressed in the science world today. He’s committed to diversity.

Rivera-Serrano’s path through academia has been far from linear — largely because of the microaggressions (which are sometimes not so micro) that he’s faced within educational institutions. He’s been approached while shopping by a construction work recruiter and told by a graduate adviser in biology to “stop talking like a Puerto Rican.”

Efra Rivera-Serrano, Ph.D.
He’s a scientist at UNC—and also a personal trainer.
Photo from @NakedCapsid Twitter

And the worst part is that he’s far from being the only one in this kind of position. That’s why Rivera-Serrano holds one simple question close to heart:

What would a cell do?

“I use this question to shape the way I tackle problems,” Rivera-Serrano says. After all, a key component of virology is the importance of intercellular communication in controlling disease spread. Similarly, a major goal of diversity-related science communication is “priming” others to fight stereotypes and biases about who belongs in science.

Virology’s “herd immunity” theory operates under the principle that higher vaccination rates mean fewer infections. For some viruses, a 90% vaccination rate is all it takes to completely eradicate an infection from existing in a population. Rivera-Serrano, therefore, hopes to use inclusive science communication as a vaccination tool of sorts to combat discriminatory practices and ideologies in science. He isn’t looking for 100% of the world to agree with him—only enough to make it work.

Herd immunity places value on community rather than individuals.
Image by Tkarcher via Wikimedia Commons

This desire for “inclusive science communication” led Rivera-Serrano to found Unique Scientists, a website that showcases and celebrates diverse scientists from across the globe. Scientists from underrepresented backgrounds can submit a biography and photo to the site and have them published for the world’s aspiring scientists to see.

Some Unique Scientists featured on Rivera-Serrano’s site!

Generating social herd immunity needs to start from an early age, and Unique Scientists has proven itself useful for this purpose. Before introducing the website, school teachers asked their students to draw a scientist. “It’s usually a man who’s white with crazy hair,” according to Rivera-Serrano. Then, they were given the same instructions after browsing through the site, and the results were remarkable.

“Having kids understand pronouns or see an African American in ecology—that’s all something you can do,” Rivera-Serrano explains. It doesn’t take an insane amount of effort to tackle this virus.

What it does take, though, is cooperation. “It’s not a one-person job, for sure,” Rivera-Serrano says. But maybe we can get there together.

Flu No More: The Search for a Universal Vaccine

By Jeremy Jacobs

On January 6, 2020

In Biology, Global Health, Immunology

Chances are, you’ve had the flu.

Body aches, chills, congestion, and cough—for millions across the globe, these symptoms are all too familiar.

Dr. Peter Palese, an Icahn School of Medicine researcher working on a universal flu vaccine.

For some, though, the flu leads to serious complications. Last year, as many as 647,000 Americans were hospitalized due to flu-related illness, with an additional 61,000 deaths.

Countless hours of lost productivity also accompany the illness. Including hospitalization costs, estimates for the flu’s total economic burden range from 10 to 25 billion dollars each year.

Flu prevention efforts have yielded mixed results. For many viruses, vaccines provide protection that lasts a lifetime, building up a network of antibodies primed to neutralize future infections. Influenza viruses, however, mutate quickly, rendering vaccines from years past ineffective. As a result, new vaccines are constantly in development.

Every year, researchers predict which flu viruses are likely to dominate the upcoming flu season. Based on these predictions, new vaccines target these specific strains. Consequentially, the effectiveness of these vaccines vary with the prediction. When a vaccine is a good match for the dominant flu strain, it can lower rates of infection by 40-50%. When it isn’t, its preventative power is far lower; in 2014, for example, the yearly influenza vaccine was only 19% effective.

Peter Palese, Ph. D, might have a better solution. Working at the Icahn School of Medicine, Palese and his team are developing a vaccine that takes a new approach to flu prevention.

Just before classes ended last month, Palese spoke at the Duke Influenza Symposium, a showcase of Duke’s current research on influenza. The symposium is part of Duke’s larger push to improve the efficacy of flu vaccination.

Palese’s vaccines work by redirecting the immune response to the influenza virus. Traditional vaccines create antibodies that target hemagglutinins, proteins found on the outermost part of influenza viruses. Hemagglutinins are divided into two regions: a head domain and a stalk domain (Fig. 1).

Fig. 1: Left: General influenza structure. Right: Hemagglutinins are divided into two regions: a head domain and a stalk. The head domain is prone to mutation and undergoes rapid change while the stalk domain is more resistant to mutation.
Source: Frontiers in Immunology

In a traditional vaccination, the head domain is immunodominant—that is, the antibodies produced by vaccines preferentially target and neutralize the head domains. However, the head domain is highly prone to mutation and varies between different strains of influenza. As a result, antibodies for one strain of the virus provide no protection against other strains.

The new vaccines pioneered by Palese and his team instead target the stalk domain, a part of hemagglutinin that mutates far slower than the head domain. The stalk is also conserved across different subtypes of the influenza virus. As a result, these vaccines should theoretically provide long-lasting protection against most strains of influenza.

Testing in ferret, mice, and guinea pigs have produced promising results. And early human trials suggest that this new kind of vaccination grants broad immunity against influenza. But long-term results remain unclear—and more trials are underway. “We would love to say it works,” Palese says. “But give us 10 years.”

In the meantime, the seasonal flu vaccine is our best option.“The recommendation to vaccinate everyone is the right policy,” Palese tells us.

Post by Jeremy Jacobs

How the Flu Vaccine Fails

By Sarah Haurin

On April 22, 2019

In Biology, Global Health, Immunology, Lecture, Medicine

Influenza is ubiquitous. Every fall, we line up to get our flu shots with the hope that we will be protected from the virus that infects 10 to 20 percent of people worldwide each year. But some years, the vaccine is less effective than others.

Every year, CDC scientists engineer a new flu virus. By examining phylogenetic relationships, which are based on shared common ancestry and relatedness, researchers identify virus strains to target with a vaccine for the following flu season.

Sometimes, they do a good job predicting which strains will flourish in the upcoming flu season; other times, they pick wrong.

Pekosz’s work has identified why certain flu seasons saw less effective vaccines.

Andrew Pekosz, PhD, is a researcher at Johns Hopkins who examines why we fail to predict strains to target with vaccines. In particular, he examines years when the vaccine was ineffective and the viruses that were most prevalent to identify properties of these strains.

A virus consists of RNA enclosed in a membrane. Vaccines function by targeting membrane proteins that facilitate movement of the viral genome into host cells that it is infecting. For the flu virus, this protein is hemagglutinin (HA). An additional membrane protein called neuraminidase (NA) allows the virus to release itself from a cell it has infected and prevents it from returning to infected cells.

The flu vaccine targets proteins on the membrane of the RNA virus. Image courtesy of scienceanimations.com.

Studying the viruses that flourished in the 2014-2015 and 2016-2017 flu seasons, Pekosz and his team have identified mutations to these surface proteins that allowed certain strains to evade the vaccine.

In the 2014-2015 season, a mutation in the HA receptor conferred an advantage to the virus, but only in the presence of the antibodies present in the vaccine. In the absence of these antibodies, this mutation was actually detrimental to the virus’s fitness. The strain was present in low numbers in the beginning of the flu season, but the selective pressure of the vaccine pushed it to become the dominant strain by the end.

The 2016-2017 flu season saw a similar pattern of mutation, but in the NA protein. The part of the virus membrane where the antibody binds, or the epitope, was covered in the mutated viral strain. Since the antibodies produced in response to the vaccine could not effectively identify the virus, the vaccine was ineffective for these mutated strains.

With the speed at which the flu virus evolves, and the fact that numerous strains can be active in any given flu season, engineering an effective vaccine is daunting. Pekosz’s findings on how these vaccines have previously failed will likely prove invaluable at combating such a persistent and common public health concern.

Post by undergraduate blogger Sarah Haurin

Tiny Bubbles of Bacterial Mischief

By Guest Post

On December 21, 2018

In Biology, Guest Post, Immunology

Margarethe (Meta) Kuehn studies vesicles — little bubbles that bud off bacterial membranes. All sorts of things may be tightly packed into these bubbles: viruses, antigens, and information a bacterium will need to make cells vulnerable to infection.

But why do bacteria produce these small membrane vesicles in the first place? Why not spread out to nearby cells themselves?

Jenny and Meta met last month on the Duke campus.

“The short answer is that we don’t know yet,” explains Kuehn, an associate professor of biochemistry at Duke. “But we speculate that it is due to their small size. These vesicles, which serve as delivery ‘bombs,’ can pass through pores that are too small for bacteria to fit through.”

Originally a chemistry major, Kuehn always had an interest in biochemistry. As an undergraduate, she worked in protein purification and then in the infectious disease division of a children’s hospital. There, she learned about pathogenic bacteria and how they secrete proteins to give themselves access to host cells.

Kuehn’s lab studies the mysterious world of bacterial vesicle production,focusing on the genetic, biochemical, and functional features of vesicles. So far, they have identified specific proteins and genes involved in the vesiculation process.

With a fine filter, they showed that vesicles can fit through holes to reach mammalian cells where a bacterium cannot.

Kuehn wonders why the bacteria don’t just use soluble proteins, which are even smaller than vesicles. They must have some reason for preferring the cell’s vesicles. Currently, they believe that vesicles can serve as nice packages — a whole bolus of information delivered together.

Basic anatomy of a vesicle, a bubble-like membrane-bound package used by cells to move things around.

Not only will this new insight into extracellular vesicles of gram-negative bacteria aid in identifying new medicines, vesicles are also being used for vaccine delivery.

“They are really good antigen vehicles,” reveals Kuehn, “The more we know how they are made, the better we can design effective vaccines for humans.”

According to Kuehn, the amazing part about studying these pathogens is that, “You are never done. You never know it all. Every single pathogen, they each do things differently.” What keeps Kuehn going, she explains, is that the search never ends.

“There is never really a defined end point; you have to come to grips with the fact that you will never know that whole answer.”

Guest Post by Jenny Huang, NCSSM 2019

HIV Can Be Treated, But Stigma Kills

By Anne Littlewood

On December 6, 2018

In Faculty, Global Health, Immunology, Medicine

Three decades ago, receiving an HIV diagnosis was comparable to being handed a death sentence. But today, this is no longer the case.

Advances in HIV research have led to treatments that can make the virus undetectable and untransmittable in less than six months, a fact that goes overlooked by many. Treatments today can make HIV entirely manageable for individuals.

However, thousands of Americans are still dying of HIV-related causes each year, regardless of the fact that HIV treatments are accessible and effective. So where is the disconnect coming from?

On the 30th anniversary of World AIDS Day, The Center for Sexual and Gender Diversity at Duke University hosted a series of events surrounding around this year’s international theme: “Know Your Status.”

One of these events was a panel discussion featuring three prominent HIV/AIDS treatment advocates on campus, Dr. Mehri McKellar, Dr. Carolyn McAllaster, and Dr. Kent Weinhold, who answered questions regarding local policy and current research at Duke.

From left to right: Kent Weinhold, Carolyn McAllaster, Mehri McKellar and moderator Jesse Mangold in Duke’s Center for Sexual and Gender Diversity

The reason HIV continues to spread and kill, Dr. McKellar explained, is less about accessibility, and more about stigma. Research has shown that stigma shame leads to poor health outcomes in HIV patients, and unfortunately, stigma shame is a huge problem in communities across the US.

Especially in the South, she said, there is very little funding for initiatives to reduce stigma surrounding HIV/AIDS, and people are suffering as a result.

In 2016, the CDC reported that the South was responsible for 52 percent of all new HIV diagnoses and 47 percent of all HIV-related deaths in the US.

If people living with HIV don’t feel supported by their community and comfortable in their environment, it makes it very difficult for them to obtain proper treatment. Dr. McKellar’s patients have told her that they don’t feel comfortable getting their medications locally because they know the local pharmacist, and they’re ashamed to be picking up HIV medications from a familiar face.

HIV/AIDS Diagnoses and Deaths in the US 1981-2007 (photo from the CDC)

In North Carolina, the law previously required HIV-positive individuals to disclose their status and use a condom with sexual partners, even if they had received treatment and could no longer transmit the virus. Violating this law resulted in prosecution and a prison sentence for many individuals, which only enforced the negative stigma surrounding HIV. Earlier this year, Dr. McAllaster helped efforts to create and pass a new version of the law, which will make life a lot easier for people living with HIV in North Carolina.

So what is Duke doing to help the cause? Well, In 2005, Duke opened the Center for AIDS Research (also known as CFAR), which is now directed by Dr. Kent Weinhold. In the last decade, they have focused their efforts mainly on improving the efficacy of the HIV vaccine. The search for a successful vaccine has been long and frustrating for CFAR and the Duke Human Vaccine Institute, but Dr. Weinhold is optimistic that they will be able to reach the realistic goal of 60 percent effectiveness in the future, although he shied away from predicting any sort of timeline for this outcome.

Pre-exposure prophylaxis or PrEP (photo from NIAID)

Duke also opened a PrEP Clinic in 2016 to provide preventative treatment for individuals who might be at risk of getting HIV. PrEP stands for pre-exposure prophylaxis, and it is a medication that is taken before exposure to HIV to prevent transmission of the virus. Put into widespread use, this treatment is another way to reduce negative HIV stigma.

The problem persists, however, that the people who most need PrEP aren’t getting it. The group that has the highest incidence of HIV is males who are young, black and gay. But the group most commonly receiving PrEP is older, white, gay men. Primary care doctors, especially in the South, often won’t prescribe PrEP either. Not because they can’t, but because they don’t support it, or don’t know enough about it.

And herein lies the problem, the panelists said: Discrimination and bias are often the results of inadequate education. The more educated people are about the truth of living with HIV, and the effectiveness of current treatments, the more empathetic they will be towards HIV-positive individuals.

There’s no reason for the toxic shame that exists nationwide, and attitudes need to change. It’s important for us to realize that in today’s world, HIV can be treated, but stigma kills.

Post by Anne Littlewood

MyD88: Villain of Allergies and Asthma

By Lydia Goff

On January 30, 2018

In Environment/Sustainability, Genetics/Genomics, Immunology, Medicine

Even if you don’t have allergies yourself, I guarantee you can list at least three people you know who have allergies. Asthma, a respiratory disorder commonly associated with allergies, afflicts over 300 million individuals worldwide.

Seddon Y. Thomas, PhD of the NIEHS

Seddon Y. Thomas who works at the National Institute of Environmental Health Sciences has been exploring how sensitization to allergens occurs. The work, which she described at a recent session of the Immunology Seminar Series, specifically focuses on the relationship between sensitization and the adaptor molecule MyD88.

MyD88 transfers signals between some of the proteins and receptors that are involved in immune responses to foreign invaders. Since allergies entail inflammation caused by an immune response, Thomas recognized that MyD88 played a role in the immune system’s sensitization to inhaled allergens.

Her research aims to discover how MyD88 alters conventional dendritic cells (cDCs) which are innate immune cells that drive allergic inflammation. MyD88 signaling in cDCs sometimes preserves open chromatin — the availability of DNA for rapid replication — which allows gene changes to happen quickly and in turn causes allergic sensitization. Open chromatin regions permit the DNA manipulation that can lead to allergies and asthma.

Florescence microscopy image of mouse dendritic cells with mRNA-loaded blood cells.

To conduct her experiments, Thomas examines what happens in mice when she deletes MyD88 from lung epithelial cells and from antigen-presenting cells. Lung epithelial cells form a protective tissue where inhaled air meets the lung and protects from foreign invaders. But sometimes it takes its job a little too seriously and reacts strongly to allergens.

Similarly, antigen-presenting cells are involved in the immune system’s mission to protect the body, but can become confused about who the enemy is. When the signaling adaptor MyD88 is removed from lung epithelial cells, the number of eosinophils, inflammatory white blood cells, decreases. When it is removed from antigen-presenting cells, another type of white blood cell, neutrophils, also decreases.

Thomas said this shows that MyD88 is necessary for the inflammation in the lungs that causes asthma and allergies.

In her future research, Thomas wishes to explore dendritic cell gene expression, the molecular pathways controlling gene expression, and how specific types of lung epithelial cells adjust immune responses. Because MyD88 plays a role in the genetic changes, it makes sense to continue research on the genetic side.

Post by Lydia Goff