Evolutionary Views of Tuberculosis

An interaction between the microbe, the host and environment, is responsible for an active Tuberculosis (TB) disease. Infected individuals may have a sub-clinical replication of the mycobacteria and be asymptomatic or have copious replication of mycobacteria and present with typical TB disease, which often results in death. Patients with a primary infection may remain asymptomatic or progress to the disease. Reactivation of the disease can occur after an asymptomatic primary infection which may develop fast within a year or take decades long. Reinfections and relapses can also occur after curing a once active TB disease. In patients with symptomatic TB, Human immunodeficiency virus (HIV) is a well-known risk factor and the HIV epidemic has contributed to a spike in TB infection. Recently, additional diagnostic tools for TB like assays that measure indoleamine 2, 3 dioxygenase-1 (IDO) activity have been proposed. This is due to the limitations of existing diagnostic assays of the causative organism of TB, Mycobacterium tuberculosis (M. tuberculosis). IDO is important in a variety of medical research fields including immunology, neurobiology, transplantation, infertility medicine and cancer. However, available information on its relevance in TB is limited.

Dr. Melinda Suchard, Clement Adu-Gyamfi and Dr. Dana Savulescu from the Centre for Vaccines and Immunology at the National Institute for Communicable Diseases, a division of the National Health Laboratory Service in Johannesburg, South Africa (also affiliated with the School of Pathology at University of the Witwatersrand), together with Dr. Bridgette Cumming from Africa Health Research Institute, explored the role of IDO in Tuberculosis from an evolutionary perspective. Their expert opinion review and recommendations show that nicotinamide synthesis catalyzed by IDO is a confluence for immunometabolism, immune tolerance, reproductive fitness and TB therapeutics. Their paper is now published in BioEssays Journal.

Tryptophan is an essential amino acid that cannot be synthesized by the human body and so, it is derived from the diet. IDO is an enzyme required for the conversion of tryptophan to kynurenines, a process important to the de novo synthesis of nicotinamide. Nicotinamide can be obtained from the diet or synthesized in the body from tryptophan and it is needed for cellular metabolism. IDO plays an important role in materno-fetal tolerance, resulting in an increase in human reproductive fitness. IDO also plays a role in immune suppression by depleting tryptophan, which is required by T lymphocytes and other mechanisms. Macrophages activated alternatively express IDO and they are suspected to have an important role in the pathogenesis of TB.

During inflammation, the activation of IDO increases the concentration of pathway products, such as nicotinamide and kynurenines while decreasing tryptophan, the pathway’s substrate. M. tuberculosis can synthesize tryptophan and nicotinamide adenine dinucleotide. Therefore, some researchers have postulated that changes in diet in the last centuries have caused an evolutionary benefit to individuals infected with M. tuberculosis, where presumably a latent infection makes up for dietary deficiency of nicotinamide or tryptophan.

Markedly elevated IDO activity has been observed in active TB infections. In addition, elevated levels of IDO have also been observed in HIV infection even without concurrent TB. The team speculate that the synergistic interaction between HIV and Tuberculosis appears to be connected to IDO activity in increasing kynurenines and decreasing tryptophan.

From this critical review of the comprehensive literature, Dr. Melinda Suchard and her colleagues were able to conclude that the pathway for nicotinamide production catalyzed by IDO is a converging point for immune tolerance, immunometabolism, reproductive fitness and TB therapeutics. They proposed that further studies with the focus on this pathway especially during latent and active TB infection will advance our knowledge on why humans remain susceptible to TB after centuries of co-evolution. It will also reveal new potential targets for the diagnosis and therapeutic management of TB.