Notre Dame Science 2019 - Biology Excellence

Study: Tuberculosis survives by using host system against itself

Rare disease stakeholders collaborate to accelerate research for cures

Scientists neutralize reactive nitrogen molecules to enhance cancer immunotherapy


Study: Tuberculosis survives by using host system against itself

By Jessica Sieff

Jeff Schorey Tb Feature

In a new study published in the Journal of Experimental Medicine, scientists at the University of Notre Dame have discovered that the pathogen Mycobacterium tuberculosis (MTB) releases RNA into infected cells. This RNA stimulates the production of a compound known as interferon beta that appears to support the growth of the pathogen.

 

As part of the study the researchers found that mice lacking a key protein required for responding to foreign RNA and therefore required for interferon beta production were better able to control the MTB infection. The discovery was a surprise to the researchers, as interferon beta is essential to controlling several viral infections.

 

“The results suggest that our immune response to mycobacterial RNA is beneficial for the pathogen and bad for the host. It’s the total opposite of viral infections,” said Jeff Schorey, George B. Craig Jr. Professor in the Department of Biological Sciences at Notre Dame and co-author of the study. “This study gives us a better understanding of how the mycobacteria causes disease and what makes it the most successful pathogen in human history.”

 

MTB infections cause a battle between the immune response and the ability of the bacteria to circumvent that response — who wins the battle determines the body’s ability to control the infection. Schorey and Yong Cheng, a research assistant professor at Notre Dame, set out to determine how mycobacteria RNA could be affecting the host response. What they found was that by releasing RNA, the bacteria set off a chain reaction inside the macrophage, a cell type of the immune system — resulting in a mechanism that benefits the survival of MTB through the production of interferon beta.

 

While researchers have long known that bacteria produce proteins and other compounds to modulate an immune response, such a role for mycobacterial nucleic acids has only recently been defined. In viral infections, as opposed to bacterial infections, the virus releases its nucleic acids as it needs the machinery of the host cell to help make viral proteins and replicate its genome. In contrast, bacteria already have the machinery for these processes in place, suggesting the release of RNA into the host cell is intentional. The authors found that the MTB use its secretion system known as SecA2 to mediate RNA release from the mycobacteria.

 

“Bacteria have everything they need to make their proteins, so the fact that they were releasing nucleic acids was a surprise,” Schorey said. “These bugs are using this RNA-sensing pathway, which has evolved to promote antiviral activity — so in other words, the bacteria are manipulating our own immune system against us.”

 

MTB is the No. 1 cause of death by an infectious organism, and kills up to 1.8 million people each year. The World Health Organization estimates 200,000 of those deaths are children. Health officials lack an effective vaccine against pulmonary tuberculosis, and antibiotics used to treat the disease must be taken for six to nine months — a daunting regimen that challenges patient compliance. The disease is prevalent in parts of the world where health care systems lack infrastructure and funding.

 

Despite those challenges, Schorey, an affiliated faculty member at Notre Dame’s Eck Institute for Global Health, said the study’s results show potential for the development of immunotherapies to selectively stimulate protective immune responses as a treatment option for MTB and other bacterial infectious diseases. 

 

The study was funded by the National Institute of Allergy and Infectious Diseases.

 


Rare disease stakeholders collaborate to accelerate research for cures

By Ellen Crowe Finan and Deanna Csomo McCool

Dr. James Wilson

Medicine and patient care for those who have rare diseases is undergoing a revolution, according to John Crowley, chairman and chief executive officer of Amicus Therapeutics and founding board member of Global Genes.

And the first question he posed to researchers, drug companies, and patient advocate groups who gathered in a working session at the University of Notre Dame in October was simple: “What role can Notre Dame and universities play in this revolution?”

A rare disease, by National Institutes of Health standards, is one that affects fewer than 200,000 people in the United States at any given time. Such diseases run the gamut from certain cancers to lysosomal storage disorders including Niemann Pick Disease Type C, which took the lives of three grandchildren of the late Notre Dame Football Coach Ara Parseghian. Patients with rare diseases often experience long roads before diagnosis, and are faced with limited therapeutic options.

The collaborative session, “Accelerating Academic Rare Disease Research and Innovation,” was sponsored by Amicus Therapeutics and drew stakeholders from across the country who discussed strategies for advancing research, bringing new drugs to market, advocating for patients, and disseminating information about rare diseases, among other topics. It was co-chaired by Crowley and Dr. Marshall Summar, division chief and genetics metabolism director of the Rare Disease Institute at Children’s National Health System in Washington D.C., as well as chairman of National Organization for Rare Disorders.

Keynote speaker Dr. James Wilson, director of the Orphan Disease Center and the Gene Therapy Program at the University of Pennsylvania, described how the development of gene therapies disrupted and displaced traditional methods of delivering treatments to patients.  “These therapies were hatched and fermented in academic centers outside of traditional business centers,” he said.

Instead of treating diseases with drugs or surgery, gene therapy delivers a gene into a cell with the goal of reprogramming it and treating the disease. When academic researchers were able to overcome the challenge of transferring genes to metabolic cells for degenerative neurological diseases around 2001, the gene therapy industry bloomed. “They are ‘one and done therapies. No pills are necessary,” Wilson explained, adding that gene therapies to treat hemophilia and muscular dystrophy have had some good results.

“The complicated part is disrupting traditional markets and getting it to patients,” he said. But this is where he believes Notre Dame can emerge as a leader, helping bring new technologies to patients by leveraging its strong relationships with politicians and legal institutions.

A stakeholder panel moderated by Crowley and Summar discussed the challenges of getting treatments for rare diseases approved by the Federal Drug Administration (FDA). Traditional FDA protocols for clinical trials are not practical for rare diseases, and make it hard to get treatments approved. The small number of patients, the progressive nature of the diseases, and the wide variations in disease were reasons noted by the panelists that make it hard to conduct clinical trials for new treatments.

“There is not the same evidence base for rare diseases as there is for cancer or other more widespread diseases,” said panelist Diana Wetmore, vice president of therapeutic development for the Harrington Discovery Institute, at University Hospitals Cleveland Medical Center. “More research is needed.”

Rare Disease Panel

Those on the panel agreed that research universities like Notre Dame can invest in models that support short-term, moderate, and long-term ideas and research, noting there can be more collaboration between researchers and pharmaceutical companies.  “Notre Dame has an opportunity to improve the delivery system and work with the legal systems and the FDA to create more flexible systems for clinical trials and to bring treatments for rare diseases forward,” said Kasturi Haldar, the Rev. Julius A. Nieuwland Professor, C.S.C., Professor of Biological Sciences and the Parsons-Quinn Director of the Boler-Parseghian Center for Rare and Neglected Diseases.

Those on a second panel, moderated by Sean Kassen, director of the Ara Parseghian Medical Research Fund, and Jayne Gershkowitz, chief patient advocate at Amicus Therapeutics, focused their discussion on the role of patient advocacy in developing treatments for rare diseases.

“No one has the passion the family has,” said panelist Jean Campbell, principal of JF Campbell Consultants and co-founder of Professional Patient Advocates in Life Science (PPALS). “When we listen to the patients, we can do the best we can with academic researchers and clinics. Patient registries are important as we move into clinics.”

Patient advocacy has changed a lot in the past ten years, noted panelist Cindy Parseghian, president and co-founder of the Ara Parseghian Medical Research Fund. The internet has made it easier to connect, but “Go Fund Me”-style initiatives have created a proliferation of fundraisers and foundations, making it more difficult to have a cohesive voice, she told the audience.

Moving the Ara Parseghian Medical Foundation from Tucson to Notre Dame resulted in a strong partnership, explained Parseghian. “Notre Dame embraced the mission and made it its own,” she said. “Researchers in academic labs and the National Institutes of Health are able to develop new compounds that could be the next drug for treating diseases.”

Overall, the working session highlighted the need for more collaboration in order to find cures for rare diseases. Partnerships among all stakeholders--foundations, academic researchers, industry, and government---are critical to bringing ideas to the forefront.

“It’s hard to be collaborative,” said panelist Jennifer Bernstein, executive vice president of Horizon Government Affairs. “Yet, that’s where the magic happens.”


Scientists neutralize reactive nitrogen molecules to enhance cancer immunotherapy

By Jessica Sieff

Xin Lu 700Xin Lu

Immunotherapy — harnessing T-cells to attack cancer cells in the body — has given hope to patients who endure round after round of treatment, including chemotherapy, to little effect. For all of its promise, however, immunotherapy still benefits only a minority of patients — a reality driving research in the field for ways to improve the relatively new approach.

One method for improving efficacy is the development of bio- and activity-based markers to better predict which patients will respond to immunotherapy and identify why some don’t. In a new study in the Proceedings of the National Academy of Sciences, researchers at the University of Notre Dame studying tumors in prostate cancer models found that nitration of an amino acid can inhibit T-cell activation, thwarting the T-cell’s ability to kill cancer cells.  

“People put a lot of hope on immunotherapy, and it has worked well for some patients, but overall the number is still low,” said Xin Lu, John M. and Mary Jo Boler Assistant Professor of Biological Sciences at Notre Dame who studies molecular understanding and immunotherapy of metastatic cancer. “By identifying activity-based markers like this one, we can design approaches that shut down the particular mechanisms that inhibit T-cell activation so immunotherapy can work.” 

In the study, Lu and his team explain how highly reactive molecules, called reactive nitrogen species (RNS), produced by myeloid-derived suppressor cells (MDSCs) cause nitration of an amino acid in a lymphocyte-specific protein called tyrosine kinase (LCK), which is crucial for T-cell activation. Nitration is a process to add a special chemical group “nitro” to the amino acid molecule, called tyrosine, in proteins. After this modification, the protein may alter its overall structure thus exhibiting different functions. MDSCs are prevalent in solid tumors that contribute to more than 90 percent of all cancers.  

Prostate cancer “is a slow progressing disease,” Lu said.  “Nevertheless, for patients with aggressive cases of prostate cancer, there is no effective treatment.”

According to the American Cancer Society, prostate cancer is the second leading cause of cancer-related death for men in the United States behind lung cancer. Lu and his team also looked at tumors in lung cancer models, and tested treatments as part of the study.

“At this moment, we don’t have an agent to block a particular amino acid from nitration,” Lu said. “But we do have ways to block nitration all together.”

Lu tested three methods of treatment to block nitration, which would keep the LCK protein active — and allow it to do its job of killing cancer cells. Treating models with an immune checkpoint blockade or uric acid, which can neutralize RNS to limited degrees, yielded little response in the tumor models.

“When we combined them, our results showed that it could suppress RNS, activate cytotoxic T cells and achieve impressive efficacy,” Lu said.

While MDSCs are highly abundant in solid tumors, they are not all alike, which is why Lu is focusing on activity taking place at the molecular level. The hope is to expand the study and investigate new antibodies capable of recognizing this particular type of modification for better prognosis.

“You can imagine in the clinic, if a patient comes in with metastatic prostate cancer from which a fine-needle biopsy can be acquired, you can look for MDSC activity using the nitrated protein biomarker and predict whether or not an agent that inhibits MDSC will be required for immunotherapy to work,” he said.

Because MDSCs are in high abundance in many types of solid tumors, Lu said it could be argued that the phenomenon found in the prostate cancer models has a high likelihood of applying to other solid tumors in other types of cancer.

“The question is how we reach more people,” Lu said. “The goal is to identify biomarkers and therapeutic targets that enhance current immunotherapies to unleash more power from these therapies. By doing this, we may benefit many more patients.”

The study was funded by an American Cancer Society Institutional Research Grant through the Harper Cancer Research Institute, with support from a Core Pilot grant from the Indiana Clinical and Translational Sciences Institute, as well as support from the Freimann Life Sciences Center and Mass Spectrometry and Proteomics Facility at Notre Dame. Lu’s research is supported by the Boler-Parseghian Center for Rare and Neglected Diseases.