From left: Jim Lederer, PhD, Josh Keegan, Anu Seshadri, MD, and Jenni Nguyen, with one of the CyTOF instruments, used to simultaneously look at multiple markers on individual cells

This is the second in a series of stories about the Brigham Research Institute Centers. The BRI includes 10 disease-focused research centers that develop and support collaborative research initiatives. This infrastructure allows our diverse community of clinicians and scientists to communicate more effectively, providing numerous opportunities for them to collaborate on research aimed at curing, treating and preventing human diseases and conditions. The story below highlights some of the exciting work happening in the Infectious and Immunologic Diseases Research Center.

Infections and our susceptibility to immunologic diseases are inextricably linked. Infectious agents, including viruses, bacteria and fungi, impact our body’s basic immune responses – which help identify and protect against foreign substances – and may play a major role in the development of immunologic diseases (such as asthma, rheumatoid arthritis, type 1 diabetes and ulcerative colitis). Investigators in the Brigham Research Institute’s Infectious and Immunologic Diseases Research Center are probing these connections and using state-of-the-art technologies to better understand their interplay as well as the impact of traumatic injury on the body’s ability to fend off infection.

Under the leadership of co-chairs Ana C. Anderson, PhD, of the Department of Neurology, Rachael Clark, MD, PhD, of the Department of Dermatology, and Matthew Waldor, MD, PhD, of the Department of Medicine, the Infectious and Immunologic Diseases Research Center supports an integrated approach to advance the prevention, diagnosis and treatment of both infectious diseases and immunologic diseases. The center brings together an interdisciplinary group of clinical and scientific investigators across six BWH departments: Dermatology, Medicine, Neurology, Obstetrics and Gynecology, Pathology and Surgery.

“The breadth of the center is quite broad, but the unifying theme is the immune system,” says Anderson. “The immune system can combat infection, but sometimes it is derailed and contributes to the disease process.”

With advancements in molecular biology, the center has been at the forefront in discovering molecules that are critical in altering the body’s immune responses to infectious agents.

Using Advanced Technology to Understand the Progression of Infectious Disease

“The infection part of the Infectious and Immunologic Diseases Research Center is focused on making new vaccines, investigating the role of commensal microorganisms (the nonharmful and often beneficial microbes that inhabit many sites in the body) in infectious diseases, and furthering our understanding of the pathogenesis of a variety of infectious diseases, including HIV,” says Waldor.

The Waldor Lab is studying pathogens that live in the intestine and cause diarrhea, including Vibrio cholerae, the cause of cholera. “We are making great strides toward developing a new live vaccine for cholera,” said Waldor.

Waldor is also excited about harnessing CRISPR-Cas9 as a technology for studies of infectious diseases.

CRISPR-Cas9 is a relatively new genome editing technology used to target and remove, add or alter specific stretches of DNA. The Waldor Lab and other laboratories within the Department of Medicine are designing genetic screens that use CRISPR-Cas9 to carry out genome-wide screens for host factors that contribute to susceptibility to infectious diseases. Waldor and his team hope to identify new potential targets for therapeutics to combat these pathogens.

Jean Lee, PhD, of the Department of Medicine, and her lab are studying Staphylococcus aureus, the cause of the majority of staph infections. With so many clinical trials failing to produce an effective staph vaccine, Lee and her lab have embarked on collaborations to develop a multi-component staph vaccine to prevent life-threatening infections caused by S. aureus.

Gerald Pier, PhD, a microbiologist in the Department of Medicine, and his lab found a surface polysaccharide, known as poly-N-acetylglucosamine (PNAG), present on many microbial pathogens. PNAG functions as a conserved capsule on the outer surface of microbes that avoids detection by the immune system of the host organism. Pier and his lab are developing a vaccine to overcome immune avoidance of PNAG and potentially prevent a variety of infections. They are currently studying the effect of the vaccine in preventing pneumonia in horses, caused by an organism producing a disease similar to that of tuberculosis in humans.

Personalizing Trauma Treatment Through Single-Cell Exploration

Three years ago, BWH, Harvard Medical School (HMS), Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Beth Israel Deaconess Medical Center and the Ragon Institute combined funds to purchase two CyTOF (mass cytometry) instruments, available to all investigators at these affiliated institutions.

“CyTOF measures individual cells and multiple markers on these cells,” said James Lederer, PhD, of the Department of Surgery and co-director of the BWH Human Immunology Center. “We can look at upwards of 45 markers simultaneously, so it’s a great systems immunology tool.”

Lederer started building specialized antibodies that can be used to identify single-cell markers, specifically for the CyTOF technology through a $130,000 grant from the Brigham Research Institute (BRI). This grant led to the creation of the BWH-BRI CyTOF Antibody Resource and Core Facility, which provides these high-quality antibodies to members of the Harvard research community.

Using CyTOF technology, Lederer has made breakthroughs in understanding how traumatic injuries affect the immune system. Traumatic injury accounts for more than 40 million emergency department visits each year and is the leading cause of death for Americans age 44 and under. When a person is injured, they become more susceptible to infections, says Lederer.

“Our goal is to understand how the immune system changes after traumatic injury so we can promote a better healing process, which includes a heightened immunity against infections,” Lederer added. “CyTOF has been revolutionary for us because when a trauma, infection or any of these complex diseases occurs, there are a lot of cells that are involved. With CyTOF, you can simultaneously look at multiple cell types and multiple markers on these cells and fully phenotype the cellular response to the injury, infection or complex disease.”

Another major advancement from this work was the discovery of a missing subset of T cells in the lungs after an infection in an animal model of traumatic injury. Lederer and his team found that missing that one subset of cells changes the whole path of the infection, making it impossible for the immune system to clear the infection.

“We couldn’t have discovered that without CyTOF technology,” says Lederer. “We’re going to keep using this technology to figure out how to personalize trauma treatments and understand what cells to target.”

Revolutionizing Cancer Treatment With Immunotherapies

Vijay Kuchroo, DVM, PhD, former co-chair of the Infectious and Immunologic Diseases Research Center and founding director of the Evergrande Center for Immunologic Diseases at HMS and BWH, is studying immunotherapies, treatments that target the immune system, for treatment of autoimmune diseases and cancer. “We are revolutionizing the way cancer patients are treated,” says Kuchroo.

The Kuchroo Laboratory discovered Tim-3, a checkpoint receptor that has been found to put a brake on T-cell responses – which are critical in detecting and attacking foreign cells – in diseases like cancer. Using checkpoint inhibitors to take the “brakes” off of the immune system, the Kuchroo Laboratory is currently involved in clinical trials exploring Tim-3 as a target for immunotherapy drugs in cancer treatment. Compared to chemotherapy, which targets tumors directly, immunotherapy uses one’s own immune system to identify and fight cancerous cells, as well as boost the individual’s immune responses.

Anderson emphasized the important role that BWH has played in bringing cancer immunotherapy to the clinic and the hospital’s unique position as a leader in both cancer research and clinical care.

“Working together, we’ve been able to make fundamental discoveries about immune biology and translate them all the way through to patient care,” said Anderson. “This is in part because of the unique resources we have through the Infectious and Immunologic Diseases Research Center, both in terms of advanced technology and our highly motivated community of investigators who are working to tackle pressing problems in new and bold ways.”

Resources for the BWH Infectious and Immunologic Diseases Community

In addition to the CyTOF Antibody Resource and Core Facility, the center is also offering two new resources to the BWH community. The first is the Infectious and Immunologic Diseases (IID) Research Scholars Program, through which IID researchers seeking funding from foundations that don’t include indirect costs can apply for funding to meet the 15-percent indirect costs minimum recently mandated by Partners. The second resource is the summer undergraduate internship, through which undergraduates can be placed in IID researchers’ labs for the summer at no cost to the lab.