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Involvement of skeletal muscle gene regulatory network in susceptibility to wound infection following trauma.

Apidianakis Y, Mindrinos MN, Xiao W, Tegos GP, Papisov MI, Hamblin MR, Davis RW, Tompkins RG, Rahme LG - PLoS ONE (2007)

Bottom Line: Despite recent advances in our understanding the pathophysiology of trauma, the basis of the predisposition of trauma patients to infection remains unclear.Our study links SMG expression and function to increased susceptibility to infection, and suggests that P. aeruginosa affects SMG homeostasis locally by restricting SMG expression in injured skeletal muscle tissue.Local potentiation of these host responses, and/or inhibition of their suppression by virulent P. aeruginosa cells, could lead to novel therapies that prevent or treat deleterious and potentially fatal infections in severely injured individuals.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts, United States of America.

ABSTRACT
Despite recent advances in our understanding the pathophysiology of trauma, the basis of the predisposition of trauma patients to infection remains unclear. A Drosophila melanogaster/Pseudomonas aeruginosa injury and infection model was used to identify host genetic components that contribute to the hyper-susceptibility to infection that follows severe trauma. We show that P. aeruginosa compromises skeletal muscle gene (SMG) expression at the injury site to promote infection. We demonstrate that activation of SMG structural components is under the control of cJun-N-terminal Kinase (JNK) Kinase, Hemipterous (Hep), and activation of this pathway promotes local resistance to P. aeruginosa in flies and mice. Our study links SMG expression and function to increased susceptibility to infection, and suggests that P. aeruginosa affects SMG homeostasis locally by restricting SMG expression in injured skeletal muscle tissue. Local potentiation of these host responses, and/or inhibition of their suppression by virulent P. aeruginosa cells, could lead to novel therapies that prevent or treat deleterious and potentially fatal infections in severely injured individuals.

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hep mediates increased resistance to thoracic, but not abdominal or systemic, infection.Survival kinetics of (A, C, E) and bacterial proliferation per fly in (B, D, F) wild-type and hep1 flies, following local PA14 infection of the thorax (A, B), or the abdomen (C, D), or systemic injector-pumping PA14 infection (E, F). Error bars indicate Standard Deviation of the mean (C, D, F) and * indicate t-test P-values of ≤0.05 (B). The difference in mortality kinetics between wild type and mutant flies is statistically significant. Detailed statistical evaluations of the survival kinetics are presented in Table S2.
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pone-0001356-g004: hep mediates increased resistance to thoracic, but not abdominal or systemic, infection.Survival kinetics of (A, C, E) and bacterial proliferation per fly in (B, D, F) wild-type and hep1 flies, following local PA14 infection of the thorax (A, B), or the abdomen (C, D), or systemic injector-pumping PA14 infection (E, F). Error bars indicate Standard Deviation of the mean (C, D, F) and * indicate t-test P-values of ≤0.05 (B). The difference in mortality kinetics between wild type and mutant flies is statistically significant. Detailed statistical evaluations of the survival kinetics are presented in Table S2.

Mentions: We compared the survival kinetics of mutant and wild-type flies after local thoracic, abdominal or systemic PA14 infection (Fig. 4A,C,E), accomplished by needle-pricking (local) or injector-mediated pumping (systemic). The hep1 flies died significantly earlier than wild-type flies after thoracic (Fig. 4A), but not after abdominal (Fig. 4C) or injector-mediated infection (Fig. 4E). Furthermore, relative to similarly treated wild-type flies, greater bacterial growth was observed in the thorax-inoculated hep1 flies (Fig. 4B), but not abdomen-inoculated (Fig. 4D) or systemically-infected (Fig. 4F) hep1 flies.


Involvement of skeletal muscle gene regulatory network in susceptibility to wound infection following trauma.

Apidianakis Y, Mindrinos MN, Xiao W, Tegos GP, Papisov MI, Hamblin MR, Davis RW, Tompkins RG, Rahme LG - PLoS ONE (2007)

hep mediates increased resistance to thoracic, but not abdominal or systemic, infection.Survival kinetics of (A, C, E) and bacterial proliferation per fly in (B, D, F) wild-type and hep1 flies, following local PA14 infection of the thorax (A, B), or the abdomen (C, D), or systemic injector-pumping PA14 infection (E, F). Error bars indicate Standard Deviation of the mean (C, D, F) and * indicate t-test P-values of ≤0.05 (B). The difference in mortality kinetics between wild type and mutant flies is statistically significant. Detailed statistical evaluations of the survival kinetics are presented in Table S2.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2131783&req=5

pone-0001356-g004: hep mediates increased resistance to thoracic, but not abdominal or systemic, infection.Survival kinetics of (A, C, E) and bacterial proliferation per fly in (B, D, F) wild-type and hep1 flies, following local PA14 infection of the thorax (A, B), or the abdomen (C, D), or systemic injector-pumping PA14 infection (E, F). Error bars indicate Standard Deviation of the mean (C, D, F) and * indicate t-test P-values of ≤0.05 (B). The difference in mortality kinetics between wild type and mutant flies is statistically significant. Detailed statistical evaluations of the survival kinetics are presented in Table S2.
Mentions: We compared the survival kinetics of mutant and wild-type flies after local thoracic, abdominal or systemic PA14 infection (Fig. 4A,C,E), accomplished by needle-pricking (local) or injector-mediated pumping (systemic). The hep1 flies died significantly earlier than wild-type flies after thoracic (Fig. 4A), but not after abdominal (Fig. 4C) or injector-mediated infection (Fig. 4E). Furthermore, relative to similarly treated wild-type flies, greater bacterial growth was observed in the thorax-inoculated hep1 flies (Fig. 4B), but not abdomen-inoculated (Fig. 4D) or systemically-infected (Fig. 4F) hep1 flies.

Bottom Line: Despite recent advances in our understanding the pathophysiology of trauma, the basis of the predisposition of trauma patients to infection remains unclear.Our study links SMG expression and function to increased susceptibility to infection, and suggests that P. aeruginosa affects SMG homeostasis locally by restricting SMG expression in injured skeletal muscle tissue.Local potentiation of these host responses, and/or inhibition of their suppression by virulent P. aeruginosa cells, could lead to novel therapies that prevent or treat deleterious and potentially fatal infections in severely injured individuals.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts, United States of America.

ABSTRACT
Despite recent advances in our understanding the pathophysiology of trauma, the basis of the predisposition of trauma patients to infection remains unclear. A Drosophila melanogaster/Pseudomonas aeruginosa injury and infection model was used to identify host genetic components that contribute to the hyper-susceptibility to infection that follows severe trauma. We show that P. aeruginosa compromises skeletal muscle gene (SMG) expression at the injury site to promote infection. We demonstrate that activation of SMG structural components is under the control of cJun-N-terminal Kinase (JNK) Kinase, Hemipterous (Hep), and activation of this pathway promotes local resistance to P. aeruginosa in flies and mice. Our study links SMG expression and function to increased susceptibility to infection, and suggests that P. aeruginosa affects SMG homeostasis locally by restricting SMG expression in injured skeletal muscle tissue. Local potentiation of these host responses, and/or inhibition of their suppression by virulent P. aeruginosa cells, could lead to novel therapies that prevent or treat deleterious and potentially fatal infections in severely injured individuals.

Show MeSH
Related in: MedlinePlus