Deceiving the big eaters: Salmonella Typhimurium protein, SopB helps in survival inside macrophages

Work done in the lab of Prof. Dipshikha Chakravortty at the Department of Microbiology and cell biology, Indian Institute of Science, Bangalore

About author

Ritika Chatterjee hails from Kolkata, India. She completed her Bachelor of Science in Microbiology (Honours) from Ashutosh College, Calcutta University (West Bengal), and her Master of Science in Biochemistry from Ballygunge Science College, Calcutta University (West Bengal). Ritika then joined Prof. Dipshikha Chakravortty’s Lab at the Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore (Karnataka), to pursue her doctorate. She worked on host-pathogen interactions, focusing on membrane fusion protein SNAREs and Salmonella interactions. She has also delved into research involving several other pathogens (belonging to the ESKAPE group) during her tenure as PhD candidate. Ritika has joined Prof. Matthias Trost’s group at Newcastle University as a Research Associate.

Interview

How would you explain your research outcomes to the non-scientific community?

Foodborne diseases are a significant public health issue worldwide, causing illness, death, and economic losses, particularly in low- and middle-income countries with limited resources for food safety management. Salmonella is a significant cause of diarrhoeal diseases globally and can be present in various foods, including meat, eggs, and dairy products, especially in regions with poor sanitation and hygiene. While effective treatments exist for most patients infected with Salmonella, those with weak immune systems are at high risk of severe and lethal outcomes. Symptoms of Salmonella infection include diarrhoea, fever, and abdominal cramps that can be severe in vulnerable populations such as young children, aged and immunocompromised individuals. In extreme cases, typhoid fever can cause complications such as intestinal perforation and death. Therefore, it is essential to investigate the pathogen’s fundamental biology and interactions with the host to develop newer therapies to manage infections better.

In this study published in Microbes and Infection journal, we investigated how Salmonella, a sneaky bacterium that can invade and survive inside immune cells, called macrophages, spreads throughout the body and cause severe infections. The immune system tries to fight back by using a defence mechanism called autophagy (bacterial autophagy is called xenophagy), a process that helps destroy bacteria. However, Salmonella has developed ways to evade this mechanism using a protein called SopB. SopB can change how host cells work by altering their chemical makeup, which allows the bacteria to avoid being destroyed by lysosomes, like “cellular garbage disposals”. Additionally, SopB can decrease the overall number of lysosomes in macrophages by reducing the function of a protein called TFEB, which is essential for lysosome formation and autophagy. This means that Salmonella can survive and spread throughout the body, causing severe infections in specialized cell like macrophages which is supposed to kill all the bugs inside the host. This study highlights the importance of understanding how bacteria interact with the host immune system so that new treatments can be developed to manage these infections better.

Figure: We report for the first time that the Salmonella pathogenicity island-1 (SPI-1) effector SopB is involved in subverting host autophagy via dual mechanisms. SopB is a phosphoinositide phosphatase capable of altering the phosphoinositide dynamics of the host cell. Here, we demonstrate that SopB mediates escape from autophagy by inhibiting the terminal fusion of Salmonella-containing vacuoles (SCVs) with lysosomes and/or autophagosomes. We also report that SopB downregulates overall lysosomal biogenesis by modulating the Akt-transcription factor EB (TFEB) axis via restricting the latter’s nuclear localization. TFEB is a master regulator of lysosomal biogenesis and autophagy. This reduces the overall lysosome content inside host macrophages, further facilitating the survival of Salmonella in macrophages and systemic dissemination of Salmonella.

How do these findings contribute to your research area?

In our study, we highlighted potential therapeutic options that could be explored further to reduce systemic Salmonella infection through macrophages. These options include small molecule inhibitors against SopB or activators of TFEB. Our findings shed light on a new aspect of Salmonella infection and its systemic effects. It is important to note that multiple pathways may be involved in the TFEB axis and maintaining homeostasis. Interestingly, previous studies have linked the TFEB axis to neurodegenerative disorders. Further research to assess the long-term risks of developing such conditions will provide novel avenues for future research in the link between the Salmonella-TFEB axis and neurodegenerative disorders domain.

“We highlighted potential therapeutic options that could be explored further to reduce systemic Salmonella infection through macrophages.”

What was the exciting moment during your research?

The most exciting moments will be when a particular experiment does not work. Then you try different troubleshooting (maybe some protocol or hypothesis changes) and find the answer to why it was not working. That is very intellectually stimulating. Apart from this, I find the complex interaction of host and pathogen intriguing because it is like a ‘tug of war’, with several layers to the never-ending arms race.

What do you hope to do next?

During my tenure at IISc, Bangalore, I thoroughly enjoyed the research process (comprising failure and successes). Therefore, I would like to pursue my career in the research field primarily focussed on host-pathogen interactions.

Where do you seek scientific inspiration from?

Two women scientists have scientifically inspired me the most. The first is Madame Marie Curie, and the second is my PhD mentor, Prof. Dipshikha Chakravortty (Department of Microbiology and Cell Biology, IISc, Bangalore); they have taught me to think critically and always strive for excellence. I always believe in a famous quote by Madame Curie “Life is not easy for any of us. But what of that? We must have perseverance and, above all, confidence in ourselves. We must believe that we are gifted with something and that this must be attained”.

How do you intend to help Indian science improve?

There is a lot of intellectual talent in our country. With increased research and development funding, we are on a path to achieving at par or even better research quality compared to several developed countries in the EU and America. We need to focus more on the engagement of the non-scientific community with the core areas of research and development that would help the majority to understand the importance of research work and its implication on the day-to-day life of people.

Reference

Ritika Chatterjee, Debalina Chaudhuri, Subba Rao Gangi Setty, Dipshikha Chakravortty, Deceiving The Big Eaters: Salmonella Typhimurium SopB subverts host cell Xenophagy in macrophages via dual mechanisms, Microbes and Infection, 2023, 105128. https://www.sciencedirect.com/science/article/abs/pii/S128645792300031X?via%3Dihub

Copy Editor

Pragya Gupta

PhD Scholar, University of Melbourne, Australia

Beside being a passionate stem cell researcher, Pragya Gupta is trained in Indian classical music, enjoys baking, inventive craftwork and learning about different cultures. She is currently doing her PhD at the University of Melbourne in Australia, where she is researching new ways to treat brain cancers.

For interview related queries, write to us at interview.biopatrika@gmail.com