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Regulation of mammalian siderophore 2,5-DHBA in the innate immune response to infection.

Liu Z, Reba S, Chen WD, Porwal SK, Boom WH, Petersen RB, Rojas R, Viswanathan R, Devireddy L - J. Exp. Med. (2014)

Bottom Line: Pathogens secrete small iron-binding moieties, siderophores, to acquire host iron.In support of this idea, supplementation with mammalian siderophore enhances bacterial growth in vitro.Thus, reciprocal regulation of 24p3 and mammalian siderophore is a protective mechanism limiting microbial access to iron.

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Affiliation: Case Comprehensive Cancer Center; Department of Pathology; Department of Medicine, Tuberculosis Research Institute and Division of Infectious Diseases; and Department of Chemistry, Case Western Reserve University, Cleveland, OH 44106Case Comprehensive Cancer Center; Department of Pathology; Department of Medicine, Tuberculosis Research Institute and Division of Infectious Diseases; and Department of Chemistry, Case Western Reserve University, Cleveland, OH 44106.

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2,5-DHBA deficient mice are resistant to E. coli infection. (A and B) WT and bdh2- mice were infected with 2.5 × 108 CFU of E. coli H9049 strain (A) or 108 CFU of E. coli 25922 strain (B) i.p. and their survival was monitored for 7 d. Data are representative of 2 independent experiments with 8–13 mice per group. Statistical analysis by log-rank test: ***, P < 0.001. (C–E) Bacterial loads in blood and parenchymal tissues of WT and bdh2- mice 36 h after infection with 0.6 × 108 CFU of E. coli H9049. Blood (C) or homogenates of liver (D) and spleen (E) were plated on LB agar plates and the CFU were determined. Symbols represent individual mice. Bars represent the mean CFU. Data are representative of two independent experiments, each with at least four mice per group. Statistical analysis by two-tailed unpaired Student’s t test with Welch’s correction: ***, P < 0.001. (F) Survival curve comparing WT and bdh2- mice after i.p. challenge with S. aureus 25923 strain (3 × 108 CFU). Mice were monitored for 4 d after challenge. Data are representative of two independent experiments with seven mice per group. Statistical analysis by log-rank test: ns, not significant. (G) Survival curve comparing WT and bdh2- mice after i.p. challenge with 7 × 107C. albicans. Mice were monitored for 3 wk after challenge. Data are representative of two independent experiments with 10 mice per group. Statistical analysis by log-rank test: ns, not significant. (H) Survival analysis of WT and bdh2- mice infected with M. tuberculosis (M. tb) H37Rv. Mice were monitored for 300 d after challenge. Each group contained 12 mice. Statistical analysis by log-rank test: ns, not significant. (I) Histological analysis of representative lung sections (H&E) from WT and bdh2- mice infected with M. tuberculosis H37Rv. Bars, 100 µM. (J) CFU determination in lung homogenates of WT and bdh2- mice infected with M. tuberculosis. Symbols represent individual mouse. Bars represent the mean CFU. Data are representative of two independent experiments, each with at least three mice per group. Statistical analysis by two-tailed unpaired Student’s t test with Welch’s correction: ns, not significant; ***, P < 0.001.
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fig3: 2,5-DHBA deficient mice are resistant to E. coli infection. (A and B) WT and bdh2- mice were infected with 2.5 × 108 CFU of E. coli H9049 strain (A) or 108 CFU of E. coli 25922 strain (B) i.p. and their survival was monitored for 7 d. Data are representative of 2 independent experiments with 8–13 mice per group. Statistical analysis by log-rank test: ***, P < 0.001. (C–E) Bacterial loads in blood and parenchymal tissues of WT and bdh2- mice 36 h after infection with 0.6 × 108 CFU of E. coli H9049. Blood (C) or homogenates of liver (D) and spleen (E) were plated on LB agar plates and the CFU were determined. Symbols represent individual mice. Bars represent the mean CFU. Data are representative of two independent experiments, each with at least four mice per group. Statistical analysis by two-tailed unpaired Student’s t test with Welch’s correction: ***, P < 0.001. (F) Survival curve comparing WT and bdh2- mice after i.p. challenge with S. aureus 25923 strain (3 × 108 CFU). Mice were monitored for 4 d after challenge. Data are representative of two independent experiments with seven mice per group. Statistical analysis by log-rank test: ns, not significant. (G) Survival curve comparing WT and bdh2- mice after i.p. challenge with 7 × 107C. albicans. Mice were monitored for 3 wk after challenge. Data are representative of two independent experiments with 10 mice per group. Statistical analysis by log-rank test: ns, not significant. (H) Survival analysis of WT and bdh2- mice infected with M. tuberculosis (M. tb) H37Rv. Mice were monitored for 300 d after challenge. Each group contained 12 mice. Statistical analysis by log-rank test: ns, not significant. (I) Histological analysis of representative lung sections (H&E) from WT and bdh2- mice infected with M. tuberculosis H37Rv. Bars, 100 µM. (J) CFU determination in lung homogenates of WT and bdh2- mice infected with M. tuberculosis. Symbols represent individual mouse. Bars represent the mean CFU. Data are representative of two independent experiments, each with at least three mice per group. Statistical analysis by two-tailed unpaired Student’s t test with Welch’s correction: ns, not significant; ***, P < 0.001.

Mentions: To test whether 2,5-DHBA–deficient mice resist E. coli infection, we challenged bdh2- mice with an acute lethal dose of a clinical strain of E. coli, H9049. As in earlier studies (Flo et al., 2004), low doses (<1.5 × 108 CFU) did not impair the survival of WT mice (unpublished data). However, a higher dose (2.5 × 108 CFU), resulted in 100% death of the WT mice by 24 h compared with 60% of bdh2- mice (Fig. 3 A). 40% of the bdh2- mice went on to recover from infection; none of the WT mice survived (Fig. 3 A). Additionally, the bacterial burden was lower when compared with WT mice (Fig. 3, C–E).


Regulation of mammalian siderophore 2,5-DHBA in the innate immune response to infection.

Liu Z, Reba S, Chen WD, Porwal SK, Boom WH, Petersen RB, Rojas R, Viswanathan R, Devireddy L - J. Exp. Med. (2014)

2,5-DHBA deficient mice are resistant to E. coli infection. (A and B) WT and bdh2- mice were infected with 2.5 × 108 CFU of E. coli H9049 strain (A) or 108 CFU of E. coli 25922 strain (B) i.p. and their survival was monitored for 7 d. Data are representative of 2 independent experiments with 8–13 mice per group. Statistical analysis by log-rank test: ***, P < 0.001. (C–E) Bacterial loads in blood and parenchymal tissues of WT and bdh2- mice 36 h after infection with 0.6 × 108 CFU of E. coli H9049. Blood (C) or homogenates of liver (D) and spleen (E) were plated on LB agar plates and the CFU were determined. Symbols represent individual mice. Bars represent the mean CFU. Data are representative of two independent experiments, each with at least four mice per group. Statistical analysis by two-tailed unpaired Student’s t test with Welch’s correction: ***, P < 0.001. (F) Survival curve comparing WT and bdh2- mice after i.p. challenge with S. aureus 25923 strain (3 × 108 CFU). Mice were monitored for 4 d after challenge. Data are representative of two independent experiments with seven mice per group. Statistical analysis by log-rank test: ns, not significant. (G) Survival curve comparing WT and bdh2- mice after i.p. challenge with 7 × 107C. albicans. Mice were monitored for 3 wk after challenge. Data are representative of two independent experiments with 10 mice per group. Statistical analysis by log-rank test: ns, not significant. (H) Survival analysis of WT and bdh2- mice infected with M. tuberculosis (M. tb) H37Rv. Mice were monitored for 300 d after challenge. Each group contained 12 mice. Statistical analysis by log-rank test: ns, not significant. (I) Histological analysis of representative lung sections (H&E) from WT and bdh2- mice infected with M. tuberculosis H37Rv. Bars, 100 µM. (J) CFU determination in lung homogenates of WT and bdh2- mice infected with M. tuberculosis. Symbols represent individual mouse. Bars represent the mean CFU. Data are representative of two independent experiments, each with at least three mice per group. Statistical analysis by two-tailed unpaired Student’s t test with Welch’s correction: ns, not significant; ***, P < 0.001.
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fig3: 2,5-DHBA deficient mice are resistant to E. coli infection. (A and B) WT and bdh2- mice were infected with 2.5 × 108 CFU of E. coli H9049 strain (A) or 108 CFU of E. coli 25922 strain (B) i.p. and their survival was monitored for 7 d. Data are representative of 2 independent experiments with 8–13 mice per group. Statistical analysis by log-rank test: ***, P < 0.001. (C–E) Bacterial loads in blood and parenchymal tissues of WT and bdh2- mice 36 h after infection with 0.6 × 108 CFU of E. coli H9049. Blood (C) or homogenates of liver (D) and spleen (E) were plated on LB agar plates and the CFU were determined. Symbols represent individual mice. Bars represent the mean CFU. Data are representative of two independent experiments, each with at least four mice per group. Statistical analysis by two-tailed unpaired Student’s t test with Welch’s correction: ***, P < 0.001. (F) Survival curve comparing WT and bdh2- mice after i.p. challenge with S. aureus 25923 strain (3 × 108 CFU). Mice were monitored for 4 d after challenge. Data are representative of two independent experiments with seven mice per group. Statistical analysis by log-rank test: ns, not significant. (G) Survival curve comparing WT and bdh2- mice after i.p. challenge with 7 × 107C. albicans. Mice were monitored for 3 wk after challenge. Data are representative of two independent experiments with 10 mice per group. Statistical analysis by log-rank test: ns, not significant. (H) Survival analysis of WT and bdh2- mice infected with M. tuberculosis (M. tb) H37Rv. Mice were monitored for 300 d after challenge. Each group contained 12 mice. Statistical analysis by log-rank test: ns, not significant. (I) Histological analysis of representative lung sections (H&E) from WT and bdh2- mice infected with M. tuberculosis H37Rv. Bars, 100 µM. (J) CFU determination in lung homogenates of WT and bdh2- mice infected with M. tuberculosis. Symbols represent individual mouse. Bars represent the mean CFU. Data are representative of two independent experiments, each with at least three mice per group. Statistical analysis by two-tailed unpaired Student’s t test with Welch’s correction: ns, not significant; ***, P < 0.001.
Mentions: To test whether 2,5-DHBA–deficient mice resist E. coli infection, we challenged bdh2- mice with an acute lethal dose of a clinical strain of E. coli, H9049. As in earlier studies (Flo et al., 2004), low doses (<1.5 × 108 CFU) did not impair the survival of WT mice (unpublished data). However, a higher dose (2.5 × 108 CFU), resulted in 100% death of the WT mice by 24 h compared with 60% of bdh2- mice (Fig. 3 A). 40% of the bdh2- mice went on to recover from infection; none of the WT mice survived (Fig. 3 A). Additionally, the bacterial burden was lower when compared with WT mice (Fig. 3, C–E).

Bottom Line: Pathogens secrete small iron-binding moieties, siderophores, to acquire host iron.In support of this idea, supplementation with mammalian siderophore enhances bacterial growth in vitro.Thus, reciprocal regulation of 24p3 and mammalian siderophore is a protective mechanism limiting microbial access to iron.

View Article: PubMed Central - HTML - PubMed

Affiliation: Case Comprehensive Cancer Center; Department of Pathology; Department of Medicine, Tuberculosis Research Institute and Division of Infectious Diseases; and Department of Chemistry, Case Western Reserve University, Cleveland, OH 44106Case Comprehensive Cancer Center; Department of Pathology; Department of Medicine, Tuberculosis Research Institute and Division of Infectious Diseases; and Department of Chemistry, Case Western Reserve University, Cleveland, OH 44106.

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Related in: MedlinePlus