Bacterial vampirism mediated through taxis to serum.

Bacteria of the family Enterobacteriaceae are associated with gastrointestinal (GI) bleeding and bacteremia and are a leading cause of death, from sepsis, for individuals with inflammatory bowel diseases. The bacterial behaviors and mechanisms underlying why these bacteria are prone to bloodstream entry remain poorly understood. Herein, we report that clinical isolates of non-typhoidal Salmonella enterica serovars, Escherichia coli, and Citrobacter koseri are rapidly attracted toward sources of human serum. To simulate GI bleeding, we utilized an injection-based microfluidics device and found that femtoliter volumes of human serum are sufficient to induce bacterial attraction to the serum source. This response is orchestrated through chemotaxis and the chemoattractant L-serine, an amino acid abundant in serum that is recognized through direct binding by the chemoreceptor Tsr. We report the first crystal structures of Salmonella Typhimurium Tsr in complex with L-serine and identify a conserved amino acid recognition motif for L-serine shared among Tsr orthologues. We find Tsr to be widely conserved among Enterobacteriaceae and numerous World Health Organization priority pathogens associated with bloodstream infections. Lastly, we find that Enterobacteriaceae use human serum as a source of nutrients for growth and that chemotaxis and the chemoreceptor Tsr provide a competitive advantage for migration into enterohemorrhagic lesions. We define this bacterial behavior of taxis toward serum, colonization of hemorrhagic lesions, and the consumption of serum nutrients as 'bacterial vampirism', which may relate to the proclivity of Enterobacteriaceae for bloodstream infections.

Sepsis is the leading cause of death in patients with inflammatory bowel disease. Individuals with this condition can experience recurrent episodes of intestinal bleeding, giving intestinal (or enteric) bacteria an entry point into the bloodstream. This puts patients at risk of developing fatal infections ­ particularly from infections caused by bacteria belonging to the Enterobacteriaceae family. However, it is not well understood why this family of bacteria are particularly prone to entering the bloodstream. Enteric bacteria commonly respond to chemicals (or chemical stimuli) in their environment. This process, known as chemotaxis, helps bacteria with a variety of tasks, such as monitoring their environment, moving to different areas within their environment or colonizing their host. Chemical stimuli are classed as 'attractants' or 'repellents', with attractants luring the bacteria to an area and repellents discouraging the bacteria from being in a specific place. Intestinal bleeds will release serum (the liquid part of blood) into the gut, which could serve as a source of chemical stimuli to attract Enterobacteriaceae into the bloodstream. To find out more, Glen, Gentry-Lear et al. first used a microfluidic device to simulate an intestinal bleed and tested the response of Enterobacteriaceae bacteria to serum. Using chemotaxis, bacteria were found to be attracted to the amino acid L-serine in the serum to which they were able to attach through a receptor called Tsr. They also consumed nutrients present in the human serum to help them grow. Experiments with intestinal tissue showed that chemotaxis attracted bacteria to bleeding blood vessels and the Tsr receptor helped them to infiltrate the blood vessels. Glen et al. termed this attraction to and feeding upon blood serum as 'bacterial vampirism'. These findings suggest that chemotaxis of Enterobacteriaceae towards L-serine in serum may be linked to their tendency to enter the bloodstream. Developing therapies that target chemotaxis in Enterobacteriaceae may provide a method for managing bloodstream infections.

Navigating contradictions: Salmonella Typhimurium chemotactic responses to conflicting chemoeffector signals show parity with bacterial growth benefits.

Many bacteria that colonize the guts of animals use chemotaxis to direct swimming motility and select sites for colonization based on sources of effectors derived from the host, diet, and microbial competitors of the local environ. The complex ecosystem of the gastrointestinal tract contains mixtures of chemoattractants and chemorepellents, but it remains poorly understood how swimming bacteria navigate conflicting signals. The enteric pathogen Salmonella Typhimurium possesses Tsr, a chemoreceptor protein that directs both chemoattraction and chemorepulsion responses, which we employed as a model to study chemotaxis in the presence of conflicting effector stimuli. We investigated how S. Typhimurium responds to human fecal matter, an effector source in the enteric lumen that contains high concentrations of indole, a bacteriostatic chemorepellent produced by the native commensals of the microbiota, and also nutrients such as l-serine, a chemoattractant. The indole concentration in human feces is more than 12-fold the concentration required for half-maximal chemorepulsion, however, we find S. Typhimurium, and various clinical isolates of non-typhoidal S. enterica serovars, are strongly attracted to liquid fecal matter. We further investigated the chemotactic responses of S. Typhimurium to titrations of indole and l-serine and revealed that chemorepulsion to indole is overridden in the presence of excess l-serine. We capture the inversion of these two opposing taxis behaviors in a phenomenon we define as "chemohalation" in which the bacteria organize into a halo around the treatment source with an interior zone of avoidance, which represents a compromise between chemoattraction and chemorepulsion. Growth analyses reveal that the chemotactic responses to these opposing effectors align chemoattraction and chemorepulsion with the relative growth of the bacteria in culture. Hence, our study supports the view that evolution has finely tuned chemotaxis to assess environmental habitability by evaluating the tradeoffs in bacterial growth based on the local combination of effectors.

Bacterial vampirism mediated through taxis to serum.

Bacteria of the family Enterobacteriaceae are associated with gastrointestinal (GI) bleeding and bacteremia and are a leading cause of death, from sepsis, for individuals with inflammatory bowel diseases. The bacterial behaviors and mechanisms underlying why these bacteria are prone to bloodstream entry remains poorly understood. Herein, we report that clinical isolates of non-typhoidal Salmonella enterica serovars, Escherichia coli, and Citrobacter koseri are rapidly attracted toward sources of human serum. To simulate GI bleeding, we utilized a custom injection-based microfluidics device and found that femtoliter volumes of human serum are sufficient to induce the bacterial population to swim toward and aggregate at the serum source. This response is orchestrated through chemotaxis, and a major chemical cue driving chemoattraction is L-serine, an amino acid abundant in serum that is recognized through direct binding by the chemoreceptor Tsr. We report the first crystal structures of Salmonella Typhimurium Tsr in complex with L-serine and identify a conserved amino acid recognition motif for L-serine shared among Tsr orthologues. By mapping the phylogenetic distribution of this chemoreceptor we found Tsr to be widely conserved among Enterobacteriaceae and numerous World Health Organization priority pathogens associated with bloodstream infections. Lastly, we find that Enterobacteriaceae use human serum as a source of nutrients for growth and that chemotaxis and the chemoreceptor Tsr provides a competitive advantage for migration into enterohaemorrhagic lesions. We term this bacterial behavior of taxis toward serum, colonization of hemorrhagic lesions, and the consumption of serum nutrients, as 'bacterial vampirism' which may relate to the proclivity of Enterobacteriaceae for bloodstream infections.

Bacterial chemotaxis in human diseases.

To infect and cause disease, bacterial pathogens must localize to specific regions of the host where they possess the metabolic and defensive acumen for survival. Motile flagellated pathogens exercise control over their localization through chemotaxis to direct motility based on the landscape of exogenous nutrients, toxins, and molecular cues sensed within the host. Here, we review advances in understanding the roles chemotaxis plays in human diseases. Chemotaxis drives pathogen colonization to sites of inflammation and injury and mediates fitness advantages through accessing host-derived nutrients from damaged tissue. Injury tropism may worsen clinical outcomes through instigating chronic inflammation and subsequent cancer development. Inhibiting bacterial chemotactic systems could act synergistically with antibacterial medicines for more effective and specific eradication.