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Demystifying pathogen strategies to evade the immune system

“If you know the enemy and know yourself, you need not fear the result of a hundred battles.”, wrote Sun Tzu, the eminent military strategist in his famous book, ‘The Art of War’.Nestled in the Biological Sciences division of the lush green IISc campus is a lab that lives up to this ideology. Led by Professor Dipankar Nandi, the lab addresses the twin questions of how pathogens cause infections and how our defense network – the immune system – responds to the infection.

One of the main research interests of the lab encompasses analysing the tactics of invading organisms. The lab currently studies the pathogen, Salmonella Typhimurium (S. Typhimurium), which causes gastroenteritis in humans. The research hopes to gain insights into the functional roles of genes expressed in the pathogen when it infects a cell. Interestingly, mice infected with S. Typhimurium display symptoms of typhoid and can be used as a model system to learn more about typhoid. In one of their investigations, the functions of an S. Typhimuriumprotein named ‘aminopeptidase’ or PepN during infection was elucidated. Aminopeptidases are enzymes that catalyse the degradation of proteins.

In this study, Prof. Nandi’s group discovered that though PepN is crucial for S. Typhimurium survival in conditions of low nutrition and high temperature, it actually has a negative effect on the growth of S.Typhimurium in infected mice. The work also indicates that this inhibitory effect is independent of the enzyme’s catalytic activity. Current projects in the lab are focused on exploring the exact mechanisms behind the diverse roles played by this versatile enzyme.

Another major area in which this lab carries out research involves the immune system’s responses to pathogen assault, and situations where the immune system fails. When an infection is too large for macrophages (specific immune cells that are amongst the first responders to an infection) to handle, they release cytokines, a set of signaling molecules to alert T-cells.The ‘T’ in T cells stands for ‘Thymus’, the organ in which these cells mature. One of the important questions the lab addresses involves diseases that cause a condition known as ‘thymic atrophy’. This condition arises when there is a considerable loss of thymocytes, which are the precursors of functional T-cells.

Using the pathogen Salmonella Typhimurium, Prof. Nandi’s lab has set up a model system to study various aspects of thymic atrophy. In one of their studies, the lab investigated the role of the intracellular signalling molecule, c-Jun NH2-terminal kinase (JNK), during thymic atrophy. The work led to the discovery that JNK is a crucial regulator of thymic atrophy. Inhibition of JNK activity reduced the death of thymocytes significantly. A potential application of this work is that drugs like inhibitors of JNK that reduce thymic atrophy, could be used to treat conditions that lead to thymic atrophy. Currently the lab is further investigating the processes occurring in thymic atrophy and efforts are underway to find more molecules that can be targeted to reduce thymic atrophy.

As Prof. Nandi’s lab marches ahead in a flurry of discoveries, they hope to gain deeper insights into the mechanisms used by pathogens to evade the immune system.

Dipankar Nandi is a Professor in the Department of Biochemistry, Indian Institute of Science, Bengaluru. He can be contacted at 91-80-22933051.