January 02, 2019

NAD+ depletion triggers programmed cell death to kill macrophages infected with Mycobacterium tuberculosis

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RS21160 Michael Niederweis 5 scr 1Michael Niederweis, Ph.D., Endowed Professor of Bacteriology in the Department of Microbiology, is the latest winner of the School of Medicine’s Featured Discovery. This initiative celebrates important research from School of Medicine faculty members. Dr. Niederweis and colleagues discovered that NAD+ depletion triggers programmed cell death to kill macrophages infected with Mycobacterium tuberculosis. This knowledge, published in Cell Reports, has revealed patient-targeted strategies to treat tuberculosis, which kills 1.4 million people and infects another 10 million each year. These strategies could include use of FDA-approved drugs that decrease necroptosis, NAD+ replenishment for patients or use of reagents that promote mitochondrial function, all in combination with antibacterial drugs that are used to treat tuberculosis. Read more from UAB News here.

The School of Medicine communications staff sat down with Dr. Niederweis to gain insights about his research, UAB and the science community.

Q: What compelled you to pursue this research?

A: This research was based on our discovery and characterization of the only known toxin of Mycobacterium tuberculosis. We showed that M. tuberculosis produces a toxin (TNT) which kills infected host cells by cleaving NAD, a key co-factor for many metabolic processes (see: UAB News, Science Blog, Science Daily). This finding explained the well-known cytotoxicity of M. tuberculosis. However, it was not clear why disrupting the metabolic pathways would lead to cell death. Many previous papers examining the deadly consequences of NAD depletion for cells by other pathways postulated a “metabolic catastrophe." I found this hard to believe because interference with key metabolic pathways such as glycolysis and subsequent ATP synthesis leads to energy loss and starvation in a cell, but should not cause cell death. My research is driven by exploring the most interesting questions and I was certainly intrigued by this conundrum.

Q: What was your most unexpected finding?

Our finding that NAD depletion by itself triggers a programmed cell death (necroptosis) was an unexpected discovery. I find it fascinating how bacteria and viruses have evolved to exploit molecular pathways in human cells to their benefit. The knowledge about these pathways offers us the opportunity to interfere with these exploits by pathogens and boost our immune system to better deal with infections.

Q: How do you feel your research will impact the science community?

I hope that our research will lead to a better understanding of the important role of NAD in human cells as an energy indicator. There are many open questions based on this discovery some of which we would like to follow. In particular, we are interested in finding out how cells sense NAD levels and how this sensing event activates necroptosis.

Q: What is your research’s relevance to human disease?

The finding that NAD depletion triggers programmed cell death to kill macrophages infected with M. tuberculosis gives us the opportunity to develop a host-targeted strategy to treat tuberculosis which could complement conventional anti-bacterial chemotherapy. However, the implications of our findings go well beyond tuberculosis. The observation that low NAD levels trigger cell death is probably important in other diseases in which NAD deficiency has already been observed, such as type 2 diabetes as well as neurological and heart diseases.

Q: How has being at UAB affected your research?

UAB and the Department of Microbiology in particular provide a fantastic research environment. The level of science at UAB is outstanding. I very much enjoy discussing science with my colleagues and the many opportunities to collaborate. The support by the Department of Microbiology and the School of Medicine in addition to our NIH funding was and is very important as it enables us to venture into new areas of research. In practical terms, this research was made much easier by a fantastic collaboration with Dr. Carlos Orihuela. When I discussed our findings with Dr. Orihuela, a colleague in the Department of Microbiology who has studied cell death induced by Streptococcus pneumoniae, he suggested to use the cell biology tools available in his lab. A postdoc in my lab, Dr. David Pajuelo and a postdoc in the Orihuela lab, Dr. Norberto Gonzales-Juarbe, started to work together on solving the question how the tuberculosis necrotizing toxin TNT kills cells.

Read the publication here.