Abstract
Melioidosis is an often-severe tropical infection caused by Burkholderia pseudomallei (Bp) with high associated morbidity and mortality. Burkholderia thailandensis (Bt) is a closely related surrogate that does not require BSL-3 conditions for study. Lactoferrin is an iron-binding glycoprotein that can modulate the innate inflammatory response. Here we investigated the impact of lactoferrin on the host immune response in melioidosis. Lactoferrin concentrations were measured in plasma from patients with melioidosis and following ex vivo stimulation of blood from healthy individuals. Bt growth was quantified in liquid media in the presence of purified and recombinant human lactoferrin. Differentiated THP-1 cells and human blood monocytes were infected with Bt in the presence of purified and recombinant human lactoferrin, and bacterial intracellular replication and cytokine responses (tumor necrosis factor-α (TNF-α), interleukin-1β and interferon-γ) were measured. In a cohort of 49 melioidosis patients, non-survivors to 28 days had significantly higher plasma lactoferrin concentrations compared to survivors (median (interquartile range (IQR)): 326 ng/ml (230–748) vs 144 ng/ml (99–277), p<0.001). In blood stimulated with heat-killed Bp, plasma lactoferrin concentration significantly increased compared to unstimulated blood (median (IQR): 424 ng/ml (349–479) vs 130 ng/ml (91–214), respectively; p<0.001). Neither purified nor recombinant human lactoferrin impaired growth of Bt in media. Lactoferrin significantly increased TNF-α production by differentiated THP-1 cells and blood monocytes after Bt infection. This phenotype was largely abrogated when Toll-like receptor 4 (TLR4) was blocked with a monoclonal antibody. In sum, lactoferrin is produced by blood cells after exposure to Bp and lactoferrin concentrations are higher in 28-day survivors in melioidosis. Lactoferrin induces proinflammatory cytokine production after Bt infection that may be TLR4 dependent.
Highlights
Melioidosis is a tropical bacterial infection which can cause pneumonia and sepsis
We analyzed whether lactoferrin impaired how the bacteria grows and found that the growth of Burkholderia thailandensis, a closely related bacterium, was not affected by the addition of lactoferrin to the media
When human immune cells, called monocytes, were infected with B. thailandensis, we found that levels of a specific inflammatory protein, tumor necrosis factor-α (TNF-α), increased after adding lactoferrin and that this effect was related to a specific immune recognition pathway called Toll-like receptor 4
Summary
Melioidosis is a tropical bacterial infection which can cause pneumonia and sepsis. The etiologic agent of melioidosis, Burkholderia pseudomallei (Bp), a Gram-negative saprophytic bacteria, causes disease following inoculation by inhalation, ingestion or cutaneous exposure [1]. Endemic to southeast Asia and parts of northern Australia, melioidosis has mortality rates upwards of 40% in certain regions, including northeast Thailand, despite appropriate antibiotic therapy [2,3]. Due to the difficulty in eradicating the facultatively intracellular pathogen, treatment regimens last several months [1]. Bp is classified as a Tier 1 select agent by the US Centers for Disease Control and Prevention. The worldwide prevalence of melioidosis is unknown and may represent a burgeoning global threat with over 160,000 cases worldwide annually [4]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
