Lactoferrin is a dynamic protein in human melioidosis and is a TLR4-dependent driver of TNF-α release in Burkholderia thailandensis infection in vitro.
Journal
PLoS neglected tropical diseases
ISSN: 1935-2735
Titre abrégé: PLoS Negl Trop Dis
Pays: United States
ID NLM: 101291488
Informations de publication
Date de publication:
08 2020
08 2020
Historique:
received:
08
01
2020
accepted:
18
06
2020
revised:
19
08
2020
pubmed:
9
8
2020
medline:
12
9
2020
entrez:
9
8
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 32764765
doi: 10.1371/journal.pntd.0008495
pii: PNTD-D-20-00006
pmc: PMC7439809
doi:
Substances chimiques
TLR4 protein, human
0
Toll-Like Receptor 4
0
Tumor Necrosis Factor-alpha
0
Lactoferrin
EC 3.4.21.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0008495Subventions
Organisme : NHLBI NIH HHS
ID : K08 HL094759
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI137111
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL113382
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM086270
Pays : United States
Organisme : Wellcome Trust
ID : 087769/Z/08/Z
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 090219/Z/09/Z
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 101103/Z/13/Z
Pays : United Kingdom
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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