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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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Loss of muscle specific expression of TpnC41C and Gst2 increases fly susceptibility to infection.Survival kinetics of flies carrying the RNAi control gene yuri (blue diamonds), versus muscle specific TpnC41C RNAi transgenic flies (red triangles), following thoracic (A) or abdominal (B) PA14 infection. (C) Homozygous flies bearing two distinct loss-of-function Gst206253/04227alleles, presented as Gst2(−/−), versus the corresponding heterozygous Gst206253/+ flies, presented as Gst2(−/+). (D) Wild-type flies, versus Gst2GS2160 loss of function flies, presented as Gst2(GS), and overexpression of the fly muscle specific gene Gst2 in the Gst2GS2160 loss of function background flies presented as Gst2(GS);Gst2 muscle following local PA14 infection of the thorax. Detailed statistical evaluations of the survival kinetics are presented in Table S2.
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pone-0001356-g003: Loss of muscle specific expression of TpnC41C and Gst2 increases fly susceptibility to infection.Survival kinetics of flies carrying the RNAi control gene yuri (blue diamonds), versus muscle specific TpnC41C RNAi transgenic flies (red triangles), following thoracic (A) or abdominal (B) PA14 infection. (C) Homozygous flies bearing two distinct loss-of-function Gst206253/04227alleles, presented as Gst2(−/−), versus the corresponding heterozygous Gst206253/+ flies, presented as Gst2(−/+). (D) Wild-type flies, versus Gst2GS2160 loss of function flies, presented as Gst2(GS), and overexpression of the fly muscle specific gene Gst2 in the Gst2GS2160 loss of function background flies presented as Gst2(GS);Gst2 muscle following local PA14 infection of the thorax. Detailed statistical evaluations of the survival kinetics are presented in Table S2.

Mentions: To assess the impact of SMG expression on susceptibility to infection, we knocked down expression of the fly skeletal muscle-specific TpnC41C gene [21] using a TpnC41C RNA hairpin construct. An ∼6.5-fold reduction in TpnC41C expression was confirmed by quantitative RT-PCR (SI Fig. S2A). TpnC41C knockdown expression rendered flies more susceptible (Table S2) to thoracic (Fig. 3A), but not abdominal (Fig. 3B), infection.


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)

Loss of muscle specific expression of TpnC41C and Gst2 increases fly susceptibility to infection.Survival kinetics of flies carrying the RNAi control gene yuri (blue diamonds), versus muscle specific TpnC41C RNAi transgenic flies (red triangles), following thoracic (A) or abdominal (B) PA14 infection. (C) Homozygous flies bearing two distinct loss-of-function Gst206253/04227alleles, presented as Gst2(−/−), versus the corresponding heterozygous Gst206253/+ flies, presented as Gst2(−/+). (D) Wild-type flies, versus Gst2GS2160 loss of function flies, presented as Gst2(GS), and overexpression of the fly muscle specific gene Gst2 in the Gst2GS2160 loss of function background flies presented as Gst2(GS);Gst2 muscle following local PA14 infection of the thorax. 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-g003: Loss of muscle specific expression of TpnC41C and Gst2 increases fly susceptibility to infection.Survival kinetics of flies carrying the RNAi control gene yuri (blue diamonds), versus muscle specific TpnC41C RNAi transgenic flies (red triangles), following thoracic (A) or abdominal (B) PA14 infection. (C) Homozygous flies bearing two distinct loss-of-function Gst206253/04227alleles, presented as Gst2(−/−), versus the corresponding heterozygous Gst206253/+ flies, presented as Gst2(−/+). (D) Wild-type flies, versus Gst2GS2160 loss of function flies, presented as Gst2(GS), and overexpression of the fly muscle specific gene Gst2 in the Gst2GS2160 loss of function background flies presented as Gst2(GS);Gst2 muscle following local PA14 infection of the thorax. Detailed statistical evaluations of the survival kinetics are presented in Table S2.
Mentions: To assess the impact of SMG expression on susceptibility to infection, we knocked down expression of the fly skeletal muscle-specific TpnC41C gene [21] using a TpnC41C RNA hairpin construct. An ∼6.5-fold reduction in TpnC41C expression was confirmed by quantitative RT-PCR (SI Fig. S2A). TpnC41C knockdown expression rendered flies more susceptible (Table S2) to thoracic (Fig. 3A), but not abdominal (Fig. 3B), infection.

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