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Lab Story: Molecular eavesdropping: reading the 'internal communication' of our immune system

Not many of us appreciate the number of pathological insults hurled at our bodies on a daily basis. We really don’t need to, since our immune systems do an exemplary job of safeguarding us from many of the microorganisms that constantly assault our bodies.

The first level of defence proffered by our body against any molecule or organism it perceives as ‘alien’ and therefore dangerous is called “innate immunity”. This form of immunity is generic in action as it attacks any ‘foreign agent’, unlike the memory-based immunity which works specifically against pathogens that our body has encountered earlier.

Prof. K. N. Balaji at the Microbiology and Cell Biology department of the Indian Institute of Science has worked on the subject of innate immunity for more than a decade, and his laboratory has contributed much to this field.

Innate immunity operates in many ways, but the first step as in any good security system, begins with the identification of the enemy. Normal, healthy individuals have a plethora of specialized white blood cells (WBCs) called macrophages, each of which are equipped with an array of molecular antennae capable of recognizing molecules that are foreign to the body. Some of these antennae are protein structures dubbed “pattern recognition receptors” or PRRs and can recognize a broad range of pathogens.

The process begins when PRRs on macrophages, recognize pathogens in our body. This is followed by the activation of various signalling mechanisms within the macrophages , with one group of molecules activating the next reminiscent of the passing on of a baton in a relay race. The molecular messengers ultimately relay the 'alert signal' to the nucleus, where the appropriate genes for defence against the intruder are activated. These begin the production of molecules that will broadcast the presence of the pathogen to the entire body, thus alerting many WBCs of various kinds. This frenzy of signalling results in the mass recruitment of fighter cells and molecules through the blood, to destroy the offending bug. Such recruitments known as inflammatory responses are the body’s first step towards dealing with potentially harmful visitors.

For instance, the Sonic Hedgehog (SHH) Pathway is a well characterized cellular signalling pathway mostly known to be associated with development of the individual from embryo to adult. Research at Prof. Balaji’s lab demonstrated the involvement of the SHH pathway in initiating an inflammatory response, when a PRR molecule known as TLR2 recognizes the bacterium that causes tuberculosis.

Prof. Balaji and his group work on multiple research projects that investigate how a host body reacts to the beginnings of a pathogen invasion. In one particularly interesting study, a group of researchers from the lab have established the molecular events following the binding of Dectin -1 (a PRR) to pathogenic fungi. They have demonstrated how the interaction which was actually supposed to evoke a signal cascade to wade off the enemy, actually inhibited the signalling response by another PRR , the TLR2. When TLR2 signalling is suppressed, susceptibility to other bacterial infections increases. Their research firstly highlights one of the many devious tactics used by pathogenic fungi to escape the body’s immune system. Secondly it also explains at the molecular level, how infection with one group of pathogenic organisms could potentially drive other less dangerous bacteria in the vicinity to turn harmful. The study was featured on the cover page of the journal Molecular and Cellular Biology.

Since inflammations involve many molecular messengers depending on which PRRs are activated, every molecular event the group uncovers adds another piece to the gigantic jigsaw of how the innate immune system works. Studies from Prof. Balaji’s lab have revealed many of the molecules involved during inflammatory responses to infectious organisms – discoveries that have high prominence in the pharmaceutical industry. Knowledge of the molecules involved in such inflammatory signal cascades allows them to design drugs that can activate, intensify or suppress specific inflammatory responses as required. Every bit of this group’s work brings us closer to fully appreciating how our immune systems contrive to protect us from all things bad and dangerous.

About the lab

K N Balaji is a Professor at the Department of Microbiology and Cell Biology, Indian Institute of Science.