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MyD88 dependent signaling contributes to protective host defense against Burkholderia pseudomallei.

Wiersinga WJ, Wieland CW, Roelofs JJ, van der Poll T - PLoS ONE (2008)

Bottom Line: First, we found that MyD88, but not TRIF, deficient whole blood leukocytes released less TNFalpha upon stimulation with B. pseudomallei compared to wild-type (WT) cells.The decreased bacterial clearance capacity of MyD88 KO mice was accompanied by a markedly reduced early pulmonary neutrophil recruitment and a diminished activation of neutrophils after infection with B. pseudomallei.MyD88 dependent signaling, but not TRIF dependent signaling, contributes to a protective host response against B. pseudomallei at least in part by causing early neutrophil recruitment towards the primary site of infection.

View Article: PubMed Central - PubMed

Affiliation: Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, Amsterdam, The Netherlands. w.j.wiersinga@amc.uva.nl

ABSTRACT

Background: Toll-like receptors (TLRs) have a central role in the recognition of pathogens and the initiation of the innate immune response. Myeloid differentiation primary-response gene 88 (MyD88) and TIR-domain-containing adaptor protein inducing IFNbeta (TRIF) are regarded as the key signaling adaptor proteins for TLRs. Melioidosis, which is endemic in SE-Asia, is a severe infection caused by the gram-negative bacterium Burkholderia pseudomallei. We here aimed to characterize the role of MyD88 and TRIF in host defense against melioidosis.

Methodology and principal findings: First, we found that MyD88, but not TRIF, deficient whole blood leukocytes released less TNFalpha upon stimulation with B. pseudomallei compared to wild-type (WT) cells. Thereafter we inoculated MyD88 knock-out (KO), TRIF mutant and WT mice intranasally with B. pseudomallei and found that MyD88 KO, but not TRIF mutant mice demonstrated a strongly accelerated lethality, which was accompanied by significantly increased bacterial loads in lungs, liver and blood, and grossly enhanced liver damage compared to WT mice. The decreased bacterial clearance capacity of MyD88 KO mice was accompanied by a markedly reduced early pulmonary neutrophil recruitment and a diminished activation of neutrophils after infection with B. pseudomallei. MyD88 KO leukocytes displayed an unaltered capacity to phagocytose and kill B. pseudomallei in vitro.

Conclusions: MyD88 dependent signaling, but not TRIF dependent signaling, contributes to a protective host response against B. pseudomallei at least in part by causing early neutrophil recruitment towards the primary site of infection.

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Related in: MedlinePlus

TRIF deficiency does not impact on bacterial outgrowth during experimental melioidosis.WT and TRIF mutant mice were intranasally infected with B. pseudomallei (5×102 CFU). Bacterial loads were measured 72 h after inoculation in lungs (A), liver (B) and blood (C). Data are mean±SEM (n = 8 per group at each time point); ns denotes not significant.
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pone-0003494-g004: TRIF deficiency does not impact on bacterial outgrowth during experimental melioidosis.WT and TRIF mutant mice were intranasally infected with B. pseudomallei (5×102 CFU). Bacterial loads were measured 72 h after inoculation in lungs (A), liver (B) and blood (C). Data are mean±SEM (n = 8 per group at each time point); ns denotes not significant.

Mentions: To obtain insight into the mechanisms underlying the accelerated mortality of MyD88 KO mice during experimental melioidosis, we infected WT and MyD88 KO mice with B. pseudomallei and sacrificed them after 24 (i.e. just before the first symptoms of illness occurred) and 72 hours (i.e. before the first deaths occurred) to determine bacterial loads in lungs (the primary site of the infection), liver and blood (to evaluate dissemination to distant body sites; Fig. 3). Relative to WT mice, MyD88 KO mice displayed strongly increased pulmonary and systemic bacterial loads at 24 and 72 hours after infection, as well as in their livers at 72 hours (Fig. 3). Conversely, similar bacterial loads in the lungs, liver and blood of WT and TRIF mutant mice were observed 72 hours after infection with B. pseudomallei (Fig. 4).


MyD88 dependent signaling contributes to protective host defense against Burkholderia pseudomallei.

Wiersinga WJ, Wieland CW, Roelofs JJ, van der Poll T - PLoS ONE (2008)

TRIF deficiency does not impact on bacterial outgrowth during experimental melioidosis.WT and TRIF mutant mice were intranasally infected with B. pseudomallei (5×102 CFU). Bacterial loads were measured 72 h after inoculation in lungs (A), liver (B) and blood (C). Data are mean±SEM (n = 8 per group at each time point); ns denotes not significant.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2566818&req=5

pone-0003494-g004: TRIF deficiency does not impact on bacterial outgrowth during experimental melioidosis.WT and TRIF mutant mice were intranasally infected with B. pseudomallei (5×102 CFU). Bacterial loads were measured 72 h after inoculation in lungs (A), liver (B) and blood (C). Data are mean±SEM (n = 8 per group at each time point); ns denotes not significant.
Mentions: To obtain insight into the mechanisms underlying the accelerated mortality of MyD88 KO mice during experimental melioidosis, we infected WT and MyD88 KO mice with B. pseudomallei and sacrificed them after 24 (i.e. just before the first symptoms of illness occurred) and 72 hours (i.e. before the first deaths occurred) to determine bacterial loads in lungs (the primary site of the infection), liver and blood (to evaluate dissemination to distant body sites; Fig. 3). Relative to WT mice, MyD88 KO mice displayed strongly increased pulmonary and systemic bacterial loads at 24 and 72 hours after infection, as well as in their livers at 72 hours (Fig. 3). Conversely, similar bacterial loads in the lungs, liver and blood of WT and TRIF mutant mice were observed 72 hours after infection with B. pseudomallei (Fig. 4).

Bottom Line: First, we found that MyD88, but not TRIF, deficient whole blood leukocytes released less TNFalpha upon stimulation with B. pseudomallei compared to wild-type (WT) cells.The decreased bacterial clearance capacity of MyD88 KO mice was accompanied by a markedly reduced early pulmonary neutrophil recruitment and a diminished activation of neutrophils after infection with B. pseudomallei.MyD88 dependent signaling, but not TRIF dependent signaling, contributes to a protective host response against B. pseudomallei at least in part by causing early neutrophil recruitment towards the primary site of infection.

View Article: PubMed Central - PubMed

Affiliation: Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, Amsterdam, The Netherlands. w.j.wiersinga@amc.uva.nl

ABSTRACT

Background: Toll-like receptors (TLRs) have a central role in the recognition of pathogens and the initiation of the innate immune response. Myeloid differentiation primary-response gene 88 (MyD88) and TIR-domain-containing adaptor protein inducing IFNbeta (TRIF) are regarded as the key signaling adaptor proteins for TLRs. Melioidosis, which is endemic in SE-Asia, is a severe infection caused by the gram-negative bacterium Burkholderia pseudomallei. We here aimed to characterize the role of MyD88 and TRIF in host defense against melioidosis.

Methodology and principal findings: First, we found that MyD88, but not TRIF, deficient whole blood leukocytes released less TNFalpha upon stimulation with B. pseudomallei compared to wild-type (WT) cells. Thereafter we inoculated MyD88 knock-out (KO), TRIF mutant and WT mice intranasally with B. pseudomallei and found that MyD88 KO, but not TRIF mutant mice demonstrated a strongly accelerated lethality, which was accompanied by significantly increased bacterial loads in lungs, liver and blood, and grossly enhanced liver damage compared to WT mice. The decreased bacterial clearance capacity of MyD88 KO mice was accompanied by a markedly reduced early pulmonary neutrophil recruitment and a diminished activation of neutrophils after infection with B. pseudomallei. MyD88 KO leukocytes displayed an unaltered capacity to phagocytose and kill B. pseudomallei in vitro.

Conclusions: MyD88 dependent signaling, but not TRIF dependent signaling, contributes to a protective host response against B. pseudomallei at least in part by causing early neutrophil recruitment towards the primary site of infection.

Show MeSH
Related in: MedlinePlus