Gene found in mice may play role in determining susceptibility to tuberculosis in humans

Gene is found in the chromosomal region that influences innate immunity to tuberculosis


Researchers from the Harvard School of Public Health studying tuberculosis resistance and susceptibility in animals have identified a gene in mice which plays a significant role in limiting the multiplication of intracellular pathogens Mycobacterium tuberculosis and Listeria monocytogenes inside host cells. The gene, Intracellular pathogen resistance 1 (Ipr1), found in the chromosome location known as sst1 (super susceptibility to tuberculosis 1), turns on a regulated cell death pathway of the bacteria-infected cells causing apoptosis and prevents catastrophic cell death, or necrosis. The findings appear in a paper in the April 7, 2005 issue of the journal Nature.

It is estimated that 8 million people are infected with tuberculosis annually with approximately 2 million of those dying from the lung disease per year. Yet only about 10 percent of people infected actually develop tuberculosis. Stress, malnutrition and other environmental factors significantly influence an individuals’ susceptibility to developing the disease. In addition, genetic factors have been known to play an important role in determining outcomes of tuberculosis infection in human and other mammalian hosts. However, individual host resistance genes such as Ipr1, involved in innate immunity for tuberculosis, have been difficult to pinpoint, because of a highly complex multigenic control of host immunity.

The researchers studied which genes might influence an individuals’ susceptibility to developing tuberculosis and found that an important genetic determinant of host resistance to tuberculosis is encoded within the region on mouse chromosome 1, which they named sst1. By identifying the Ipr1 gene within the sst1 region they believe they have uncovered a new mechanism that helps in limiting the possibility of developing M. tuberculosis, especially in the lungs.

Of interest, the Ipr1 gene also controls innate immunity to another intracellular pathogen Listeria monocytogenes, a parasitic disease transferred to humans generally from consuming infected animal products and that causes flu-like symptoms, swelling of the brain and for pregnant women potential loss of fetus. That suggests that the Ipr1 gene controls a general mechanism that protects against other intracellular pathogens besides M. tuberculosis. The researchers suggest that the human equivalent of Ipr1 might be a gene described as SP110 and may play a significant role in determining tuberculosis susceptibility in people.

Igor Kramnik, assistant professor of immunology and infectious disease at the Harvard School of Public Health and senior author of the study said, “The findings are encouraging and highlight the role of genetic function in determining whether a person has a high risk of developing tuberculosis. Finding a specific gene in a mouse that has a human equivalent within a highly conserved genetic region suggests that the human equivalent may also be involved in innate immunity to the disease and may further lead to development of diagnostic tests and prevention approaches.” He added, “Further studies of the Ipr1 gene in a mouse model and its counterpart in humans will improve our understanding of how our immune system works during complex interactions with live, and very successful, pathogens.”

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http://www.hsph.harvard.edu

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