Slaying vampirism in enteric bacteria
Bacterial vampirism has been identified in the Enterobacteriaceae family, revealing the link between sepsis and IBD, and highlighting new avenues for therapeutic development.
Primarily seen as the domain of Transylvanian Counts, cave-dwelling bats and sparkly skinned high schoolers, vampiric activity has now been uncovered in a new realm: gut bacteria. This finding was born from a collaborative scheming of researchers at the University of Oregon (OR, USA) and Washington State University (WA, USA), who used a multimodal approach to demonstrate that enteric bacteria are actively attracted to, and even consume, blood serum. The study could prove fruitful for the development of therapeutics to help prevent sepsis in at-risk populations.
Inflammatory bowel disease (IBD) can come with a host of symptoms, not least of which is the repetitive incidence of intestinal bleeding, providing bacteria in the intestines with an opportunity to enter the bloodstream. As a result, sepsis is the dominant cause of death in people living with IBD, predominantly from pathogens in the Enterobacteriaceae family, colloquially referred to as enteric bacteria.
It is well known that Enterobacteriaceae respond to chemical stimuli in their environment and can move towards or away from ‘attractant’ or ‘repellent’ chemical signals. However, the precise mechanism that they use to infect the blood remains shrouded in mystery.
The team developed their own investigational wooden stake to get to the heart of this mechanism and the pathogenesis of Enterobacteriaceae-induced sepsis in IBD patients: a custom injection-based microfluidic device, named chemosensory injection rig assay (CIRA). This device allowed the team to inject tiny amounts of human blood serum into a sample of motile bacteria to simulate gastrointestinal bleeding in vitro and observe their reaction using an inverted Nikon Ti2 Eclipse microscope.
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Having observed the taxis (unidirectional movement) of enteric bacteria towards the serum, the team set out to identify the primary bacterial chemoreceptor and corresponding chemoattractant within serum responsible for this movement. Suspecting a known chemoreceptor, called taxis to serine and repellents (Tsr), which only binds to the L- enantiomer of serine, the team treated the serum used in their microfluidic device with the enzyme serine racemase, which converts L- to D-serine. When this treated serum was used in CIRA, they saw a significant reduction in the attraction of the enteric bacteria, S. Typhimurium, towards the serum, indicating that Tsr and L-serine represent the Count Dracula and Mina Harker of this interaction respectively.
Further experiments using CIRA in combination with buffer solutions containing varying concentrations of different potential chemoattractants revealed that L-serine was the primary factor attracting S. Typhimurium towards the serum. Investigations in intestinal tissue revealed that Tsr not only drove the attraction of the bacteria towards blood serum, but actively aided the infiltration of blood vessels. What’s more, micromedia containing small amounts of serum boosted the proliferation of enteric bacteria, indicating that serum is used as a nutrient source for the pathogens. Taken together, the team labeled this activity “bacterial vampirism”.
These studies were followed by experiments to crystalize Tsr in complex with L-serine and determine its structure using x-ray diffraction. Though structures of this complex have previously been defined, they were not at a high enough resolution to determine key characteristics. The crystal structures provided by this study represent the first of Salmonella Typhimurium Tsr specifically, in complex with L-serine.
From these structures, the team was able to characterize them at a high enough resolution to determine an amino acid recognition motif for L-serine that is conserved among variants of Tsr in different species, providing vital information for the development of therapeutics to target this receptor. Phylogenic mapping activities conducted by the team revealed that Tsr itself is conserved throughout the Enterobacteriaceae family and a number of other pathogens associated with bloodstream infections.
This interdisciplinary approach has provided researchers and drug developers with the groundwork from which they can begin to design therapies to manage IBD-associated sepsis and other bloodstream infections. We must hope that by casting a clear beam of sunlight on these conditions, bacterial vampirism can be slayed once and for all.
