Tuberculosis (TB) is one of the deadliest infectious diseases in the world, affecting 9.6 million people worldwide in 2015, of which 2.2 million were in India. Although tuberculosis is curable through antibiotics, the increasing prevalence of multi-drug resistant forms of TB has become a major concern. A new study from the lab of Prof. Krishnamurthy Natarajan at the University of Delhi, uncovers new mechanisms through which the TB microbe interacts with cells of the host immune system, hijacking their function and preventing them from doing their job properly. The findings of the study point to new ways of treating patients afflicted with drug-resistant TB.
The TB microbe is an ingenious villain, forever scheming to evade its captors – the immune system. It does this through molecular interactions with cells of the host immune system, a phenomenon known as host-pathogen interactions. However, the molecular details of the interactions and their effect on the function of the immune system remain poorly understood. In order to understand the findings of Prof. Natarajan’s group, we need to understand the sophisticated defense mechanisms employed by the human immune system to fight against invading microbes.
Macrophages (from the Greek ‘makros’ – large, and ‘phagein’ – to eat) are large white blood cells that patrol the body and whose main function is to ingest or ‘eat’ foreign microbes. When confronted with invading microbes, macrophages also activate what is known as the innate immune response; this includes the production of reactive oxygen species (ROS), which have bactericidal properties, and the initiation of inflammatory cascades, which recruits other immune cells to the site of infection.
In a further ingenious mechanism, macrophages also undergo programmed suicide – a process called apoptosis – with the microbes inside. This denies the invading microbe a safe haven for replication and helps in preventing the spread of infection by sequestering the microbes in the macrophages’ dying bodies. Further, macrophages also undergo regulated degradation of cell components – a process called autophagy – after ingesting the microbes, which ensures that the microbes are efficiently degraded.
Crucial to macrophages’ ability to trigger the innate immune response is the maintenance of a certain concentration of calcium ions within the cell, relative to the concentration outside the cell – a process called calcium homeostasis. Certain channels present in the macrophage membrane called voltage-gated calcium channels (VGCCs) are known to play an important role in maintaining calcium homeostasis. Prof. Natarajan’s group and others have previously shown that infection with the tuberculosis microbe results in the expression of abnormally high numbers of VGCCs on the macrophage membrane, which leads to a disruption in calcium homeostasis. In this study, they looked at the effect of disrupted calcium homeostasis on the protective responses of macrophages.
The team studied the various responses of macrophages grown on Petri dishes, when infected with the tuberculosis microbe, and also when artificially stimulated by a chemical that blocked calcium influx into the macrophages. They found that infection along with VGCC stimulation caused a decrease in the production of reactive oxygen species, reduced levels of programmed cell death (apoptosis), reduced levels of regulated cell degradation (autophagy) and reduced pro-inflammatory factors. In other words, the TB microbe disrupted calcium homeostasis within macrophages to prevent them from launching the innate immune response.
The host-pathogen interactions uncovered in this study shed new light on the potential mechanisms through which drug-resistant tuberculosis develops. Deepika Sharma, the lead author of the study, commented, “The pathways seem to point towards creating conditions favorable for long-term persistence for the pathogen. Exploring and then exploiting these pathways would constitute our future endeavors.”
Previous work by Prof. Natarajan’s group identified VGCCs as a potential drug target for drug-resistant tuberculosis. The findings of this study lend credence to the proposed addition of VGCC-inhibitor drugs such as Verapamil and Amlodipine (used in the treatment of hypertension and heart rhythm disorders) to the TB drug regimen.
Prof. Natarajan is a proponent of ‘drug repurposing’, where drugs prescribed for other disorders can be explored for their beneficial effects on infections like tuberculosis. Extolling the virtue of this approach, Natarajan says, “The way forward would be to screen as many drugs as possible for combating some of the diseases like tuberculosis, HIV-AIDS, dengue, chikungunya, and infections caused by Staphylococcus aureus and Streptococcus pneumoniae, etc.”.