Dr. Delia Goletti is fighting TB at Italy’s National Institute for Infectious Diseases (INMI) in Rome and had taken part in enhancements of QuantiFERON.
Dr. Delia Goletti heads a team of seven and sees about 15 patients a week. INMI is the reference center for tuberculosis in central and southern Italy, and takes in about 300 cases a year (mostly immigrants) including rare cases of drug-resistant TB. Goletti’s lab is also working with Professor Gian Maria Fimia’s group from the University of Salento, in Lecce, Italy. Their work shows that tuberculosis inhibits autophagy, the process by which a cell gets id of unnecessary particles and also controls the replication of bacteria. TB is not a new germ, like HIV was in the 1980s or SARS was two decades later. On the contrary, the disease has been around for as long as mankind, and the bacterium at its root has been known for more than a century. It does not spread as easily as measles, rubella or influenza, but without treatment, drug-resistant TB has a mortality rate that is similar to Ebola’s.
What makes it so difficult to defeat, Dr. Goletti?
Dr. Delia Goletti: There are different reasons. Good socioeconomic conditions are the best defense against Mycobacterium tuberculosis, the bacteria that causes TB. That is why the infection thrives in developing countries where malnutrition weakens the immune system of the poorest people. In most developed countries, improved nutrition and hygiene were enough to turn tuberculosis into a rare disease by the early 1950s. Which, paradoxically, led to a second major problem: wealthy nations shifted their attention away from TB to other health issues.
Which had been a mistake?
When I was in Bethesda, Maryland, at the National Institutes of Health, we realized there was a new epidemic due to co-infection with HIV. By turning off the immune system, HIV, paves the way for tuberculosis, which, in turn, helps HIV replicate faster. About 400,000 people a year die from co-infection with HIV and TB. This does affect also wealthy nations, furthermore as life expectancy grows, there are more and more things that can weaken the immune system in addition to the natural aging process and unleash the disease, for instance therapies for autoimmune disorders or diabetes.
How to tackle that problem?
Our goal is to develop easy and quick tests that can tell who has a dormant infection, who is progressing towards the active disease, and who has active tuberculosis. Working with the latest version of the QuantiFERON test, the QFT-Plus, we can beside CD4 T-cells also measure the CD8 lymphocyte reaction. We’ve been looking for antigens that cause a reaction only during the disease, as well as antigens that only show up in latent infections. And we’ve been experimenting with different readouts, test formats, biological
samples – for example trying to use urine instead of blood.
Could that insight lead to new therapeutic strategies?
By better understanding this process it might become possible to stage the disease and spot at-risk subjects. This may open up new therapeutic strategies. It may be possible to use candidate “antigens of latency” as Rv-2628, a protein that Mycobacterium tuberculosis produces when it is starved of oxygen, as happens during latent infection.
How did you find that out?
When we measured in blood samples, this antigen provokes a much lower response in sick patients with TB than in those simply infected. More important, it seems to offer a way to date the infection. It may be an important discovery because recently infected patients are considered at higher risk of developing the disease.
Other breakthroughs likely to come?
Very interesting seems analyzing gene expression of LTBI patients. Early study results conducted in South Africa suggest that patients who are progressing to active disease, exhibit a specific 16 gene signature which could be used to identify those at risk and reduce the number of unnecessary treatments. While this approach still must be validated in larger clinical studies, it holds great promise for the development of novel predictive tests to improve the management of LTBI infections.