The paper in nature Microbiology is here: http://go.nature.com/2n8zqd0
Vibrio cholerae, the causative agent of the diarrheal disease cholera, infects millions of people each year. Most susceptible are the young, the old, and those in the midst of civil unrest or natural disaster. Many of the 200+ V. cholerae serotypes discovered so far have been found in association with arthropod species, including insects, but the ecology and evolution of this pathogen with environmental hosts remains poorly understood.
Over the past ten years, the Watnick lab at Boston Children’s Hospital has exploited the powerful genetics of the model invertebrate Drosophila melanogaster to understand the interaction of V. cholerae with the host intestine. The quorum sensing project emerged from the peculiar observation that, in contrast to many V. cholerae strains tested in the lab, which kill the fly within a few days, the Peruvian strain C6706 isolated in 1991 colonized the fly gut with relatively little mortality. Coincidentally, strains from the more recent Haitian outbreak isolated from 2010 to 2016 behaved similarly to C6706. All these strains had functional quorum sensing (QS) machinery, which allows these bacteria to maintain a social lifestyle by coordinating their behavior through an exchange of chemical signals.
When high cell density is reached in a test tube, the V. cholerae QS machinery represses virulence genes required for intestinal colonization and osmotic diarrhea, but a role for QS in tamping down virulence has never been observed in a mammalian host, and the selective advantage of maintaining an active QS system is poorly understood. We hypothesized that V. cholerae quorum sensing might be suppressing virulence in the fly. To test this, we genetically inactivated QS signaling (QS-) in the C6706 strain and several Haitian strains. We found that inactivation of QS did not impact the ability of V. cholerae to colonize the fly gut, but it did accelerate host mortality. Two recent studies from our laboratory have shown that V. cholerae metabolism plays an important role in Drosophila mortality. Therefore, we hypothesized that quorum sensing might regulate V. cholerae metabolism. To investigate this, we used polar metabolomics to compare the metabolomes of isogenic QS+ and QS- strains. This pointed to us to intermediates in the tricarboxylic acid (TCA) cycle and, in particular, succinate, which was more avidly consumed by the QS- strain. Furthermore, we could prolong survival by supplementing a QS- infection with this TCA intermediate.
How does V. cholerae succinate consumption drive host mortality? While the full mechanism is still being investigated, we have already gleaned some insights. Fly mortality is caused by a rapid depletion of lipid stores during infection with QS- strains. In fact, survival of flies infected with the QS- strain can be prolonged by genetically blocking mobilization of triglycerides from adipose tissue. Mammalian and arthropod hosts depend on the metabolic signals generated by intestinal bacteria to maintain homeostasis. While pathogens can disrupt homeostasis by consuming these metabolic signals, our study reveals a novel role for V. cholerae quorum sensing in repressing bacterial consumption of succinate to ensure nutritional cooperation of this pathogen with its arthropod host. It will be exciting to see if this is a paradigm for the interactions of other bacterial pathogens with their hosts.
Adam Wong, Audrey Vanhove, and Paula Watnick