Role of Toll-Like Receptor 5 (TLR5) in Experimental Melioidosis

Emma Birnie, Tassili A. F. Weehuizen, Jacqueline M. Lankelma, Hanna K. de Jong, Gavin C. K. W. Koh, Miriam H. P. van Lieshout, Joris J. T. H. Roelofs, Andries E. Budding, Alex F. de Vos, Tom van der Poll, W. Joost Wiersinga

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

The Gram-negative intracellular pathogen Burkholderia pseudomallei is the causative agent of melioidosis, an important cause of sepsis in Southeast Asia. Recognition of pathogen-associated molecular patterns by Toll-like receptors (TLRs) is essential for an appropriate immune response during pathogen invasion. In patients with melioidosis, TLR5 is the most abundantly expressed TLR, and a hypofunctional TLR5 variant has been associated with improved survival. Here, we studied the functional role of TLR5 and its ligand flagellin in experimental melioidosis. First, we observed differential TLR5 expression in the pulmonary and hepatic compartments upon infection with B. pseudomallei Next, we found that B. pseudomallei-challenged TLR5-deficient (Tlr5-/- ) mice were more susceptible to infection than wild-type (WT) mice, as demonstrated by higher systemic bacterial loads, increased organ injury, and impaired survival. Lung bacterial loads were not different between the two groups. The phenotype was flagellin independent; no difference in in vivo virulence was observed for the flagellin-lacking mutant MM36 compared to the wild-type B. pseudomallei strain 1026b. Tlr5-/- mice showed a similar impaired antibacterial defense when infected with MM36 or 1026b. Ex vivo experiments showed that TLR5-deficient macrophages display markedly impaired phagocytosis of B. pseudomallei In conclusion, these data suggest that TLR5 deficiency has a detrimental flagellin-independent effect on the host response against pulmonary B. pseudomallei infection.
Original languageEnglish
JournalInfection and Immunity
Volume87
Issue number8
DOIs
Publication statusPublished - 2019

Cite this

Birnie, E., Weehuizen, T. A. F., Lankelma, J. M., de Jong, H. K., Koh, G. C. K. W., van Lieshout, M. H. P., ... Wiersinga, W. J. (2019). Role of Toll-Like Receptor 5 (TLR5) in Experimental Melioidosis. Infection and Immunity, 87(8). https://doi.org/10.1128/IAI.00409-18
Birnie, Emma ; Weehuizen, Tassili A. F. ; Lankelma, Jacqueline M. ; de Jong, Hanna K. ; Koh, Gavin C. K. W. ; van Lieshout, Miriam H. P. ; Roelofs, Joris J. T. H. ; Budding, Andries E. ; de Vos, Alex F. ; van der Poll, Tom ; Wiersinga, W. Joost. / Role of Toll-Like Receptor 5 (TLR5) in Experimental Melioidosis. In: Infection and Immunity. 2019 ; Vol. 87, No. 8.
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abstract = "The Gram-negative intracellular pathogen Burkholderia pseudomallei is the causative agent of melioidosis, an important cause of sepsis in Southeast Asia. Recognition of pathogen-associated molecular patterns by Toll-like receptors (TLRs) is essential for an appropriate immune response during pathogen invasion. In patients with melioidosis, TLR5 is the most abundantly expressed TLR, and a hypofunctional TLR5 variant has been associated with improved survival. Here, we studied the functional role of TLR5 and its ligand flagellin in experimental melioidosis. First, we observed differential TLR5 expression in the pulmonary and hepatic compartments upon infection with B. pseudomallei Next, we found that B. pseudomallei-challenged TLR5-deficient (Tlr5-/- ) mice were more susceptible to infection than wild-type (WT) mice, as demonstrated by higher systemic bacterial loads, increased organ injury, and impaired survival. Lung bacterial loads were not different between the two groups. The phenotype was flagellin independent; no difference in in vivo virulence was observed for the flagellin-lacking mutant MM36 compared to the wild-type B. pseudomallei strain 1026b. Tlr5-/- mice showed a similar impaired antibacterial defense when infected with MM36 or 1026b. Ex vivo experiments showed that TLR5-deficient macrophages display markedly impaired phagocytosis of B. pseudomallei In conclusion, these data suggest that TLR5 deficiency has a detrimental flagellin-independent effect on the host response against pulmonary B. pseudomallei infection.",
author = "Emma Birnie and Weehuizen, {Tassili A. F.} and Lankelma, {Jacqueline M.} and {de Jong}, {Hanna K.} and Koh, {Gavin C. K. W.} and {van Lieshout}, {Miriam H. P.} and Roelofs, {Joris J. T. H.} and Budding, {Andries E.} and {de Vos}, {Alex F.} and {van der Poll}, Tom and Wiersinga, {W. Joost}",
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language = "English",
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Birnie, E, Weehuizen, TAF, Lankelma, JM, de Jong, HK, Koh, GCKW, van Lieshout, MHP, Roelofs, JJTH, Budding, AE, de Vos, AF, van der Poll, T & Wiersinga, WJ 2019, 'Role of Toll-Like Receptor 5 (TLR5) in Experimental Melioidosis' Infection and Immunity, vol. 87, no. 8. https://doi.org/10.1128/IAI.00409-18

Role of Toll-Like Receptor 5 (TLR5) in Experimental Melioidosis. / Birnie, Emma; Weehuizen, Tassili A. F.; Lankelma, Jacqueline M.; de Jong, Hanna K.; Koh, Gavin C. K. W.; van Lieshout, Miriam H. P.; Roelofs, Joris J. T. H.; Budding, Andries E.; de Vos, Alex F.; van der Poll, Tom; Wiersinga, W. Joost.

In: Infection and Immunity, Vol. 87, No. 8, 2019.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Role of Toll-Like Receptor 5 (TLR5) in Experimental Melioidosis

AU - Birnie, Emma

AU - Weehuizen, Tassili A. F.

AU - Lankelma, Jacqueline M.

AU - de Jong, Hanna K.

AU - Koh, Gavin C. K. W.

AU - van Lieshout, Miriam H. P.

AU - Roelofs, Joris J. T. H.

AU - Budding, Andries E.

AU - de Vos, Alex F.

AU - van der Poll, Tom

AU - Wiersinga, W. Joost

PY - 2019

Y1 - 2019

N2 - The Gram-negative intracellular pathogen Burkholderia pseudomallei is the causative agent of melioidosis, an important cause of sepsis in Southeast Asia. Recognition of pathogen-associated molecular patterns by Toll-like receptors (TLRs) is essential for an appropriate immune response during pathogen invasion. In patients with melioidosis, TLR5 is the most abundantly expressed TLR, and a hypofunctional TLR5 variant has been associated with improved survival. Here, we studied the functional role of TLR5 and its ligand flagellin in experimental melioidosis. First, we observed differential TLR5 expression in the pulmonary and hepatic compartments upon infection with B. pseudomallei Next, we found that B. pseudomallei-challenged TLR5-deficient (Tlr5-/- ) mice were more susceptible to infection than wild-type (WT) mice, as demonstrated by higher systemic bacterial loads, increased organ injury, and impaired survival. Lung bacterial loads were not different between the two groups. The phenotype was flagellin independent; no difference in in vivo virulence was observed for the flagellin-lacking mutant MM36 compared to the wild-type B. pseudomallei strain 1026b. Tlr5-/- mice showed a similar impaired antibacterial defense when infected with MM36 or 1026b. Ex vivo experiments showed that TLR5-deficient macrophages display markedly impaired phagocytosis of B. pseudomallei In conclusion, these data suggest that TLR5 deficiency has a detrimental flagellin-independent effect on the host response against pulmonary B. pseudomallei infection.

AB - The Gram-negative intracellular pathogen Burkholderia pseudomallei is the causative agent of melioidosis, an important cause of sepsis in Southeast Asia. Recognition of pathogen-associated molecular patterns by Toll-like receptors (TLRs) is essential for an appropriate immune response during pathogen invasion. In patients with melioidosis, TLR5 is the most abundantly expressed TLR, and a hypofunctional TLR5 variant has been associated with improved survival. Here, we studied the functional role of TLR5 and its ligand flagellin in experimental melioidosis. First, we observed differential TLR5 expression in the pulmonary and hepatic compartments upon infection with B. pseudomallei Next, we found that B. pseudomallei-challenged TLR5-deficient (Tlr5-/- ) mice were more susceptible to infection than wild-type (WT) mice, as demonstrated by higher systemic bacterial loads, increased organ injury, and impaired survival. Lung bacterial loads were not different between the two groups. The phenotype was flagellin independent; no difference in in vivo virulence was observed for the flagellin-lacking mutant MM36 compared to the wild-type B. pseudomallei strain 1026b. Tlr5-/- mice showed a similar impaired antibacterial defense when infected with MM36 or 1026b. Ex vivo experiments showed that TLR5-deficient macrophages display markedly impaired phagocytosis of B. pseudomallei In conclusion, these data suggest that TLR5 deficiency has a detrimental flagellin-independent effect on the host response against pulmonary B. pseudomallei infection.

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UR - https://www.ncbi.nlm.nih.gov/pubmed/31109950

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DO - 10.1128/IAI.00409-18

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