Bacterial chemotaxis in human diseases

Abstract

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.

Keywords: bacterial pathogenesis; chemotaxis; chronic inflammation; motility.

Fig. 1.. Bacterial chemotaxis across atomic, molecular, cellular, and population scales.

A. Chemoreceptors can recognize chemoeffectors through direct binding. McpN from Pseudomonas aeruginosa is shown binding nitrate at the interface between two chemoreceptor monomers (dark and light brown, PDB 6gcv [86]). Hydrogen bonds between the proteins and nitrate ligand are shown as cyan lines. B. Chemoreceptor core signaling unit [8], [104] and the canonical phosphorelay of bacterial chemotaxis. Distance between the chemoreceptor complex and flagellar rotor not to scale. C. Chemoreceptor nanoarrays amplify chemoeffector sensing [8], [104]. D. Bacterial swimming and reorientation bias in chemoeffector gradients. Hypothetical bacterium swimming trajectories are depicted as dashed lines. E-G. Chemotactic responses by motile bacterial populations absent chemoeffector, or to central sources of chemoattractant or chemorepellent. Size bars are indicated. See Figure S1 for in vitro methods of measuring chemotactic responses at the atomic, molecular, cellular, and population scales.

Fig. 2.. Disease and mortality associated with chemotactic WHO_pp.

A. Typical infection sites associated with human disease for select chemotactic pathogens are indicated, along with their priority designation by WHO. B. Estimated annual infections worldwide by pathogen: PA; Pseudomonas aeruginosa, HP; Helicobacter pylori, C; Campylobacter spp., SE; Salmonella enterica (all serovars), EC; Escherichia coli. Estimate of H. pylori annual infections is based on that the bacteria infect approximately half of the world’s total population (a). C. Annual deaths associated with antimicrobial resistance worldwide. Estimates based on data from [105]. H. pylori is not typically associated with deaths from acute infection and so is omitted (b). D. Speculative estimates for deaths associated with select diseases of inflammation and cancer are shown. Estimates are based on risk factors associated with bacterial infections based on available data: “Antibiotic Resistance Threats in the United States” https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf, “WHO publishes list of bacteria for which new antibiotics are urgently needed” https://www.who.int/news/item/27-02-2017-who-publishes-list-of-bacteria-for-which-new-antibiotics-are-urgently-needed, “Population-based Prospective Study of the Combined Influence of Cigarette Smoking and Helicobacter pylori Infection on Gastric Cancer Incidence: The Hisayama Study” https://academic.oup.com/aje/article/168/12/1409/155955, “Guillain-Barré Syndrome” https://www.cdc.gov/campylobacter/guillain-barre.html, and [106]. P. aeruginosa and E. coli are agents suspected to instigate diseases of chronic inflammation and cancers, but we did not identify literature describing specific risk factors associated with these diseases (c, d).

Fig. 3.. Evolution of chemoeffector gradients during disease progression.

A. A generalized model of the host environment during infection. Chemotactic pathogens (cyan cells) localize to nutrient sources and host tissue. After initial colonization pathogens shift toward sessility (gray cells), with some cells departing aggregates and biofilms to act as chemotactic “opportunity seekers” to colonize new regions (gray to cyan arrows). Host inflammatory responses and RONS generation (orange) can result in tissue damage (red) through phagocyte transmigration, and disrupt luminal O₂ gradients (pink). Most infections resolve, but some may progress to chronic or cancerous stages (dashed lines). B. Motile and chemotactic versus sessile fraction of pathogen populations as a function of disease progression. C. Gradients of chemoeffectors, nutrients, and toxins relevant to pathogen colonization as a function of disease progression.

Fig. 4.. Pathogen chemoattraction to sites of host injury.

A-B. H. pylori exhibits chemoattraction to injured murine gastric tissue (A), and with murine gastric organoids (B). Injury was induced through single-cell photo-damage (asterisks). See also Movie S1 for the full video. Data from [61], [62], used with permission. C. Chemoattractants present at sites of injury and in human serum. The concentration of chemoattractants in blood/serum (red arrows), or produced through phagocyte oxidants (black arrows) are noted in parentheses, and the chemoreceptors involved in direct binding and sensing of the chemoattractants (blue) are indicated. Structures of chemoreceptor ligand-binding domains are shown for select WHO_pp, with chemoeffector ligands in orange. For most of the interactions depicted it is unknown whether the presence of the chemoattractant within serum/damaged tissue mediates injury tropism. Trg senses glucose and galactose through galactose-binding protein (GBP); the structure shown is for GBP bound to galactose, denoted with “a.” Alphafold2 models are shown for Tlp11/CcrG and Tlp10 from C. jejuni, and TlpD from H. pylori, denoted with “b.” Chemoeffector concentrations are indicated. D. H. pylori chemoattraction to HOCl in vitro. A time-course of H. pylori chemotactic responses to the neutrophilic oxidant HOCl is shown pre-treatment (Pre) and at indicated timepoints. At time 0 s, a micropipette containing buffered 10 mM HOCl is inserted (yellow), and the motile bacteria in the field of view accumulate. At 60 s the HOCl source is removed and the bacteria disperse. Panels represent min-projections of 0.5 s at each time point. Data from [85], used with permission. See also Movie S2 for the full video.

Fig. 5.. Impact of omeprazole on H. pylori chemotaxis and colonization topography.

A. Chemotaxis-dependent localization is indicated by orange arrows. Chemotactic sensing of gastric pH gradients (yellow to blue) guides H. pylori to the neutral juxtamucosal mucus layer (green). Through chemotaxis, H. pylori invades gastric glands and establishes persistent bacterial reservoirs that seed expansion to new glands [26]. B. Omeprazole treatment inhibits parietal cell acid secretion in the corpus, enabling the bacteria to expand through chemotaxis to the corpus glands. Data from [94], used with permission.

Diversity of bacterial taxis behaviors

Bacteria exhibit a wide range of taxis behaviors across biology whereby bacterial populations control localization through stimuli that trigger swimming reorientations (see Figure 1 in main text). In this review we have used ‘chemotaxis’ as an umbrella term for these collective phenomena and to keep the concepts herein approachable to non-experts. However, the field utilizes more precise terminology to distinguish taxis behaviors based on mechanism and the type and source of stimuli. Bacterial swimming behaviors can be influenced by gravity (geotaxis), light (phototaxis), magnetic fields (magnetotaxis), fluid current (rheotaxis), pH conditions (pH taxis), temperature (thermotaxis), osmolarity (osmotaxis), oxygen concentrations (aerotaxis), redox potentials (energy taxis or redox taxis), and forces in vortices (gyrotaxis) [110]. The distinction between the mechanisms of chemotaxis and energy taxis is that the former relates to direct recognition of the chemoeffector ligand, typically originating from an exogenous source, whereas the latter relates to sensing internal metabolic changes induced by stimuli, such as through changes to pools of flavin redox potentials or zinc homeostasis (Figure I) [15]. Cases exist where a taxis behavior may fall into more than one of the aforementioned categories, or stimuli may elicit multiple taxis behaviors. An exemplar is the family of aerotaxis chemoreceptors (Aer), which are well documented as playing important roles in pathogenicity. Some Aer chemoreceptors mediate aerotaxis through direct sensing of O2 via heme [111,112], and others perform energy taxis by monitoring flavin adenine dinucleotide oxidoreduction [113]. S. enterica uses Aer and energy taxis for attraction to host-derived nitrate, which contributes to invasion of Peyer’s patches [11].