MedicalResearch.com Interview with:
Catherine M. Stein, PhD
Associate professor of epidemiology and biostatistics
Case Western Reserve
Dr. Stein is a leader of international research on resistance to Mycobacterium tuberculosis (MTB) infection
MedicalResearch: What is the background for this study? What do you hope to learn?
Dr. Stein: In a 2002 study, we began to clinically characterize people who lived in households where there were infectious tuberculosis cases. We followed them for a two-year period and noticed that approximately 9 percent of household members were resistant to Mycobacterium tuberculosis (MTB) infection, even though they were highly exposed to the organism. This finding surprised us because the prevailing notion had been that everyone living in TB-endemic settings or living with someone who has TB would become infected eventually. After several years of study, we found a substantial number of these people who do not have any evidence for MTB infection, so we wanted to do studies to learn if we could figure out why.
MedicalResearch: Is MTB resistance a new phenomenon? Do MTB resisters react to a tuberculin purified protein derivative (PPD) or a gold immunoassay but don’t develop clinical disease?
Dr. Stein: We don’t have any reason to believe that MTB-infection resistance is a new phenomenon. It’s just that no one has thought to look for it before. In terms of the PPD or gold immunoassays, MTB-resisters produce a negative response to both tests. The way gold immunoassays are done, three tubes are collected. One is a control. Another is a test for reacting to MTB. Still another is a positive control to make sure immune cells are alive. The MTB-resisters show a response to that positive control but not to MTB. It’s not that these patients don’t have an immune response. It’s just that they have no response to MTB, which means they have no previous exposure to cause their T-cells to make that response.
MedicalResearch: Are MTB-resisters immune to the newer multi-drug resistant strains of TB?
Dr. Stein: Resistance to MTB infection is independent of the drug resistance pattern of the bacteria. Thus we would expect them to resist multidrug resistant (MDR)-TB as well. There is no strong evidence that MDR-TB is more aggressive or virulent.
MedicalResearch: Is MTB-resistance seen in other populations around the world?
Dr. Stein: No one has looked. We at Case Western Reserve and Makerere University in Kampala, Uganda, are the first group to characterize this phenotype. We at Case Western Reserve have collaborators in South Africa who study diamond and coal miners, and preliminary data suggests MTB-resistance in that group as well. That’s a population with high MTB and HIV prevalence, and within this population, a group has emerged that is potentially resistant to MTB infection. I have also been contacted by a group in Indonesia where the same MTB infection-resistant phenomenon appears to be emerging, and that group is trying to replicate our study of MTB-resisters. No one has had the same long-term study that we have conducted of MTB-resisters, but it is likely that MTB-resistance may exist in other populations in the world. Hopefully, more researchers will engage in this study of MTB infection-resistance. In other words, we don’t believe this is unique to Uganda.
News Release from Case Western Reserve University School of Medicine
Case Western Reserve to Lead International Research on Resistance to Infection with Bacteria-Causing Tuberculosis (TB)
Scientists Seek Novel Prevention and Treatment Strategies
CLEVELAND – April 3, 2015 – After discovering a unique group of people resistant to tuberculosis (TB) infection, Case Western Reserve researchers are leading an international team dedicated to understanding exactly how they fight off a disease that claims 1.5 million lives each year.
The team’s goal is to use lessons learned from these resistant individuals to develop an approach to treating and curing TB that is unlike any existing medication. By taking cues directly from the bodies of those who consistently avoid infections, the researchers hope develop more effective approaches to defeating the disease — even in regions where current methods have fallen short.
Over the past 25 years, global health efforts have reduced the TB fatality rate by nearly half, yet the disease still stands as the world’s second-most deadly, behind only HIV/AIDS. In addition, the rate of people contracting multi-drug resistant forms of the disease has been climbing. Finally, some places still experience high rates of infection. Africa, for example, has 200 new cases per 100,000 people.
“Science has made extraordinary gains in the battle against TB, but much more progress is needed,” said Catherine M. Stein, PhD, associate professor of epidemiology and biostatistics at Case Western Reserve and a leader of the new project. “Existing methods have not proven adequate in developing nations — in particular in sub-Saharan Africa, where it is a major health concern.”
This latest project builds on more than a decade of increasingly precise studies involving Case Western Reserve, the University of Washington and Makerere University and Mulago Hospital, both in the capital city of Kampala, Uganda. The efforts began with comprehensive efforts to identify those who regularly withstand infections of all forms of TB, including the multi-drug resistant form. TB infections arising from Mycobacterium tuberculosis (MTB) bacteria, also known as tubercle bacilli, are the cause of human TB, one of the major sources of illness and death of adults in the world.
These people stand out even more because their resistance still holds when in extended and close proximity to highly contagious individuals. Once the researchers identified this unique cohort, they examined environmental factors, then biologic ones and even potential immunologic and genetic influences.
This new initiative combines a $3.5 million award from the National Institutes of Health and a $650,000 grant from the Bill & Melinda Gates Foundation. The team is concentrating on the lungs — the most regular site of TB infections. The researchers will examine the phenotypes — in essence, all of the observable characteristics of genes in those with and without infections — as well as gene expression — the process and content of instructions the gene provides for the formation of molecules, usually proteins.
Professor of medicine W. Henry Boom, MD, also the director of the Tuberculosis Research Unit at Case Western Reserve, has collaborated closely with Stein on each of the stages of the work, and will serve as a co-principal investigator with Stein, also a Genetics Working Group leader in the TB Research Unit. Harriet Mayanja-Kizza, MBChB, dean of the Makerere University Medical School, will serve as Ugandan principal investigator, with assistance of co-investigator, Ezekiel Mupere, MBChB, a pediatrician and epidemiologist at Makerere. Case Western Reserve and Makerere have been collaborators for more than a quarter century.
Mayanja-Kizza and Mupere supervise a team of medical officers and home health nurses in casting a wide net in Uganda to trace those who resist MTB infection and those who do not. At the University of Washington in Seattle, Tom Hawn, MD, PhD, professor of medicine, and Chetan Seshadri, MD, assistant professor of medicine, will provide leadership in human innate immune responses, which are most likely responsible for resistance to MTB infection.
“By focusing on these MTB-resisters, there is the potential to figure out what it is about their natural immunity that keeps them from acquiring and/or resisting MTB infection and to replicate this response with a vaccine to prevent MTB infection,” Stein said. “As far as genetic contributions, there are ways to force genes to take action, and it may be possible to turn those genes on or off to resist MTB. It may be as simple as finding genes that enhance a person’s natural immunity.”
MedicalResearch.com Interview with: Catherine M. Stein, PhD (2015). Researchers Discover Some Individuals Are Naturally Resistant To TB