Deciphering the signaling and regulatory function of the bacterial alarmones (p)ppGpp during anaerobic lifestyle – AnaeroP

The stringent response is a general bacterial stress response allowing bacteria to adapt and cope with environmental stress. This associated reprogramming of cell physiology is caused by the intracellular accumulation of the signaling molecules (p)ppGpp that are synthetized by the RelA/SpoT homolog proteins. Although studied for 60 years, the molecular mechanisms by which environmental cues activate the stringent response are still largely unknown and represent an unsolved problem in prokaryotic molecular biology. In addition, the factors that control and influence (p)ppGpp homeostasis remain poorly defined while being responsible for the outcome of the stringent response. We recently observed that the small subunit of the nitrite reductase NirD, a key regulator of nitric oxide homeostasis during anaerobic respiration, can promote bacterial fitness by adjusting (p)ppGpp levels under anaerobic conditions through physical interaction with the alarmone synthetase RelA in the gut bacterium Escherichia coli. This observation represents the first physiological evidence linking (p)ppGpp homeostasis to anaerobic metabolism in E. coli. Adaptation to environments with different oxygen tension (e.g. along the gastro-intestinal tract) is vital for growth and competitiveness but also for successful colonization of the host by facultative anaerobic pathogenic bacteria and to cause diseases. Importantly, the analysis of the stringent response in E. coli or Salmonella has so far been exclusively conducted under aerobic conditions. Accordingly, the impact of (p)ppGpp signaling under anaerobic conditions is an overlooked question and represents a relevant and emerging new research topic. Therefore, AnaeroP is an ambitious multidisciplinary program, bringing together a new consortium of three partners with complementary skills and resources, that aims at deciphering the fundamental basis of the regulatory and signaling network of the (p)ppGpp alarmones under anaerobiosis. In particular, by using state of the art approaches we will address (i) the physiological role of (p)ppGpp signaling during anaerobiosis (ii) how (p)ppGpp promotes reprogramming of cell physiology (iii) the molecular mechanisms controlling (p)ppGpp homeostasis. During the last 60 years of research, many functions have been attributed to the alarmone (p)ppGpp and it is important to point that the stringent response appears to play a key role in many aspects of bacterial cell physiology including virulence, immune evasion, and antibiotic tolerance. Therefore, by answering these fundamental questions, the outcome of the AnaeroP project will lead to fascinating new insights in our understanding of (p)ppGpp biology, adaptation and bacterial survival and we anticipate that it is likely to pave the way for the development and improvement of biotechnological processes to fight bacterial infections.