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TB: Researchers Look for New Tools to Fight Ancient Foe

Tuberculosis (TB) is an ancient disease that has afflicted humans since the dawn of civilization and remains very much with us even now. In fact, more people will probably die from TB in 2016 than from any other single infectious disease, with HIV a close second.

This grim fact is well documented by annual reports published by the World Health Organization since 1990. But it seems at odds with what we see as we look around our local Bronx neighborhood and throughout most of North America and the developed world.

Dr. Porcelli discusses what drew him to study TB and what motivates young scientists.

Indeed, most cases of TB are curable with available drug treatment, and procedures for identifying and isolating active cases have been applied with great results in wealthier countries. Yet these measures often can’t be effectively applied or are simply not possible in many resource-poor African, Asian and South American countries. There the epidemic rages on, with at best modest gains in reducing the global burden of disease.

While the prevalence of and mortality rates from TB have been gradually falling in many of the high-incidence countries for the past several years, nearly 10 million people are likely to fall ill with TB in 2016, with annual deaths from the disease exceeding 1 million globally. 

What makes tuberculosis deadly
Two features of Mycobacterium tuberculosis, the bacterium that causes TB, are responsible for its status as the most successful and deadly of human pathogens: its ability to enter a persistent state, and its extremely sophisticated strategy of immune evasion.

Thanks to a knack for persisting in tissues of infected people without causing overt disease, M. tuberculosis has been able to colonize the bodies of vast numbers of humans. Data suggest that as many as one third of all people on earth may harbor persistent TB bacteria in their bodies during their lives. These organisms may remain latent for many years, only to reactivate later and lead to illness in their hosts and transmission of the disease to others. Once in its persistent state, M. tuberculosis becomes extremely difficult to eradicate using antibiotic drugs unless those drugs are given continuously for months.

In addition, the bacterium’s ability to shut down a whole range of host immune mechanisms makes it resistant to elimination by the body’s natural defenses. This resistance extends to efforts to develop vaccines against TB, which so far have proven only modestly effective at best. 

TB therapy strategies at Einstein
Researchers at Einstein are seeking new strategies to address the problem of TB by focusing directly on the two key issues of persistence and immune evasion.

Dr. Bill Jacobs is leading an effort to define the gene expression and metabolic profiles that characterize the persistent state of the bacteria. Work by his lab has already revealed specific groups of genes that are turned on or off when the bacterium enters its persistent state. Further research is aimed at finding ways to wake up the latent bacteria, to make them more susceptible to eradication by currently available or newly developed antibiotic drugs.

My own research group focuses mainly on decoding the elaborate immune evasion strategy of M. tuberculosis. We’ve emphasized understanding the T-cell response to TB infection and how the bacterium inhibits or misdirects  it.  We recently found a gene in M. tuberculosis that encodes a protein that blocks injected macrophages and other host cells from being able to present bacterial antigens to T cells. What I find truly remarkable is that this gene is just one member of a family of more than 60 related M. tuberculosis genes. This suggests a truly staggering level of complexity and sophistication in this pathogen’s immune evasion program.

Other Einstein laboratories such as those of Drs. John Chan, Jacqueline Achkar and, Michelle Larson are studying how M. tuberculosis adapts to conditions inside macrophages, and how it resists a variety of mechanisms for immune recognition. Some of this work focuses on the possibility of dguiding antibody responses to more effectively attack the bacterium. This approach to TB treatment was largely discounted for many years, but has recently received renewed interest in the field. By pursuing multiple avenues of research, we hope to discover weaknesses in the strategy of this clever bacterium and then to exploit these weaknesses through new vaccines.  Ultimately, these research efforts could provide the advantage we need in the struggle with TB and finally allow us to put this ancient scourge to rest.

For more background on Einstein’s TB research efforts, please see this article from Einstein Magazine.

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