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.