New Study Offers Insights into Genetic Susceptibility to Tuberculosis

Since Robert Koch's discovery of the tuberculosis (TB) bacterium in 1882, scientists have developed several effective diagnostic technologies, treatments, and vaccinations for the disease. Yet, more than a century later, the World Health Organization (WHO) estimates that approximately one-third of the world's population is still infected with M. tuberculosis and nearly two million people die annually as a result. Given the rising prevalence of the disease and the emergence of multi-drug resistant strains, several research groups across the globe have been working towards developing more effective strategies to combat this epidemic.

One question that has puzzled scientists for years is why some individuals who are infected with TB show no signs while others display severe symptoms that can lead to death. With the understanding of this phenomenon, it may be possible to develop novel treatments for those who do suffer from severe TB. A recent study led by Lalita Ramakrishnan at the University of Washington has offered important insights into this question. In this study, she and her colleagues identified a gene that controls susceptibility to disease once an individual becomes infected with TB.

Known as LTA4H, the gene was identified through a screen of zebrafish larvae infected with tuberculosis. The scientists found that zebrafish heterozygous for the functional LTA4H gene experienced far less severe symptoms than those with two functional copies or two nonfunctional copies of the gene. Their studies revealed that zebrafish lacking both copies of the functional LTA4H had reduced inflammatory activity, which is necessary for combating bacterial infection. On the other hand, zebrafish with two functional copies of the gene were found to exhibit excessive inflammation, which can also be detrimental since it causes tissue damage. Zebrafish that were heterozygous for the LTA4H gene obtained an optimal balance of inflammation during infection, and are thus thought to exhibit reduced susceptibility to TB.

The researchers' findings in zebrafish were seen in human populations as well. Among patients with active TB in Vietnam, the prevalence of heterozygotes was found to be very rare, which suggests that heterozygosity for this gene may be protective against TB. This insight into the genetic basis of TB susceptibility provides an increasing understanding of the disease itself. Their findings may pave the way for new developments in more effective therapeutic options to treat those susceptible to the disease. As Ramakrishnan pointed out, "If we could keep this pathway from inciting the host immune system, we may be well on the way to finding innovative new therapies against TB, as well as other serious disorders." The results of this study have implications for chronic conditions as well, as imbalanced inflammation can lead to asthma, cancer, and certain kinds of heart and blood-vessel problems.

References:

Tobin, et al. 2010. "The lta4h locus modulates susceptibility to mycobacterial infection in zebrafish and humans". Cell 140: 717-730.

World Health Organization (WHO), The Stop TB Partnership. "A human rights approach to tuberculosis". 2001.

Author: Eanas Aboobaker

Reviewed by: Natasha Hochlowski, Selby Cull, and Yangguang Ou

Published by: Maria Huang

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