New treatment principle for tuberculosis activates the body's own defence system

Widespread resistance to antibiotics requires new, expensive medicines with various side-effects to be used against tubercle bacteria. However, many affected countries lack access to such medicines. Researchers are therefore trying to develop new strategies for  effective treatment of tuberculosis, which continues to be a major worldwide problem.

The researchers behind the new study are investigating how to activate the body's own antibiotics, antimicrobial peptides, which form a part of the innate immune defence system. The peptides are produced in all mucus membranes and also in granulocytes and macrophages, two types of white blood cells that are recruited to the site of infection.

“We have focused particularly on increasing the body's production of the body's own peptides with the help of existing drugs. LL-37, a human antimicrobial peptide that we discovered in 1995, is highly effective against TB bacteria,” says Birgitta Agerberth at the Department of Laboratory Medicine at Karolinska Institutet, one of the researchers who has led the study.

Researchers have already shown that the drugs vitamin D and phenylbutyrate increase the production of LL-37. They have now demonstrated that LL-37 plays a key role in the manner in which these drugs kill the TB bacteria. It is already known that vitamin D can trigger a process known as autophagy which is important for killing pathogenic bacteria  inside macrophages and other cells. In this study, researchers have shown that phenylbutyrate also activates autophagy   and that  vitamin D and phenylbutyrate  work even more effectively when used in combination. In addition,  the underlying mechanism of the activation has been clarified.

In an another study from the same research group it is  shown that supplementary treatment with phenylbutyrate and vitamin D had positive results when combined with standard antibiotics in the treatment of newly diagnosed tuberculosis patients in Dhaka, Bangladesh.

“The results show that we can thus strengthen the body's defence against serious infections such as tuberculosis by increasing the production of antimicrobial peptides. Both these studies provide combined support for a new treatment principle for infectious diseases with the activation of the body's own defence system combined with traditional antibiotic treatments. This new treatment strategy as we name “Host-Directed Therapy” has many advantages: it minimise the risk of developing resistance, it strengthens the effect of regular antibiotics and controls the often damaging inflammation that occurs commonly in different infections,” says Birgitta Agerberth.

The research is funded by the Swedish Foundation for Strategic Research, Swedish Heart-Lung Foundation, the Swedish Research Council and SIDA, among others.

Publication

Phenylbutyrate induces LL-37-dependent autophagy and intracellular killing of Mycobacterium tuberculosis in human macrophages

Rokeya Sultana Rekha, SSV Jagadeeswararao Muvva, Min Wan, Rubhana Raqib, Peter Bergman, Susanna Brighenti, Gudmundur H. Gudmundsson, Birgitta Agerberth

Autophagy, online 29 July 2015, doi:10.1080/15548627.2015.1075110

Source: Karolinska Institutet