TY - JOUR
T1 - Lactoferrin is a dynamic protein in human melioidosis and is a tlr4-dependent driver of tnf-α release in burkholderia thailandensis infection in vitro
AU - Wright, Shelton W.
AU - Lovelace-Macon, Lara
AU - Ducken, Deirdre
AU - Tandhavanant, Sarunporn
AU - Teparrukkul, Prapit
AU - Hantrakun, Viriya
AU - Limmathurotsakul, Direk
AU - Chantratita, Narisara
AU - Eoin West, T.
N1 - Publisher Copyright:
© 2020 Wright et al.
PY - 2020/8
Y1 - 2020/8
N2 - 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 investi-gated 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 recombi-nant 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 mono-clonal antibody. In sum, lactoferrin is produced by blood cells after exposure to Bp and lacto-ferrin concentrations are higher in 28-day survivors in melioidosis. Lactoferrin induces proinflammatory cytokine production after Bt infection that may be TLR4 dependent.
AB - 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 investi-gated 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 recombi-nant 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 mono-clonal antibody. In sum, lactoferrin is produced by blood cells after exposure to Bp and lacto-ferrin concentrations are higher in 28-day survivors in melioidosis. Lactoferrin induces proinflammatory cytokine production after Bt infection that may be TLR4 dependent.
UR - http://www.scopus.com/inward/record.url?scp=85089768384&partnerID=8YFLogxK
U2 - 10.1371/journal.pntd.0008495
DO - 10.1371/journal.pntd.0008495
M3 - Article
C2 - 32764765
AN - SCOPUS:85089768384
SN - 1935-2727
VL - 14
SP - 1
EP - 18
JO - PLoS Neglected Tropical Diseases
JF - PLoS Neglected Tropical Diseases
IS - 8
M1 - e0008495
ER -