These results suggest the possibility of tailoring tuberculosis treatment, based on a patient's genetic sequence at a gene called LTA4H, which controls the balance between pro-inflammatory and anti-inflammatory substances produced during an infection.
Tuberculosis can take hold if disease-fighting inflammation is either too weak or too strong. The strength of the response is in part the result of a person's LTA4H gene sequence. Knowing whether a patient has the gene sequence for one extreme response or the other could help guide medication decisions.
Lalita Ramakrishnan of the University of Washington said that the study suggested that that increased TB disease severity in humans can occur for fundamentally opposite reasons. "The ability to tailor therapies to these divergent inflammatory states, based on a patient's sequence at LTA4H, could improve patient outcomes."
This important observation for people began with a study of the tiny zebrafish. In these animals, the researchers linked mutations in the zebrafish version of the LTA4H gene to increased susceptibility to a TB-like infection.
After they understood the biological basis of susceptibility to infection in the zebrafish, the researchers turned to the same gene in humans. They identified a sequence of the gene that led to higher activity and increased inflammation. They then collaborated with other researchers at the University of Washington and researchers in Vietnam and the U.K. to study the gene among patients in Vietnam with TB. They discovered that patients carrying one copy of the high-activity sequence of the gene and one copy of the low-activity sequence were relatively protected from TB meningitis, a particularly deadly form of TB. Surprisingly, people with two copies of the high-activity sequence of the gene fared just as poorly as people with two copies of the low-activity sequence. This "heterozygous advantage," or "Goldilocks effect," is an unusual finding in human genetics.
This surprising finding, the researchers noted, implicated both insufficient and overly abundant inflammation as different ways TB could take hold in the body. By analysing clinical data from patients in Vietnam with a particularly severe form of TB called TB meningitis, the researchers found that anti-inflammatory therapy only benefited patients with the gene sequence that corresponds to excess inflammation. The patients with the insufficient inflammation gene sequence derived no benefit from what has been adopted as a standard therapy for TB meningitis.
MEDICA.de; Source: University of Washington