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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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Highly virulent P. aeruginosa actively restricts skeletal muscle gene induction within 1 h post-inoculation.Relative expression ratio levels of 20 fly genes that encode proteins with essential functions of thorax skeletal muscle, under different conditions: 1, 6, and 12 h after thoracic injury only (A), thoracic injury and PA14 inoculation (B), or thoracic injury and CF5 inoculation (C); 1 h following thoracic injury and co-infection with 100∶100 and 200∶100 PA14:CF5 CFUs/fly (D); or following abdominal injury alone or together with inoculation with PA14 or CF5 (E). The relative expression ratio levels of selected SMGs for each condition were calculated versus naïve. The statistical evaluation of differences in expression values between PA14 and CF5 inoculated flies is presented in Table S1.
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pone-0001356-g001: Highly virulent P. aeruginosa actively restricts skeletal muscle gene induction within 1 h post-inoculation.Relative expression ratio levels of 20 fly genes that encode proteins with essential functions of thorax skeletal muscle, under different conditions: 1, 6, and 12 h after thoracic injury only (A), thoracic injury and PA14 inoculation (B), or thoracic injury and CF5 inoculation (C); 1 h following thoracic injury and co-infection with 100∶100 and 200∶100 PA14:CF5 CFUs/fly (D); or following abdominal injury alone or together with inoculation with PA14 or CF5 (E). The relative expression ratio levels of selected SMGs for each condition were calculated versus naïve. The statistical evaluation of differences in expression values between PA14 and CF5 inoculated flies is presented in Table S1.

Mentions: In a previous study we profiled and compared the host responses that underlie susceptible versus non-susceptible D. melanogaster-P. aeruginosa interactions using PA14 and CF5 [6], two human P. aeruginosa isolates that are highly virulent and non-virulent in flies, respectively [8]. Our results showed that the fly whole genome expression responses to thorax infection by these two strains were strikingly different. We identified pathogenesis- and defense-specific genes with putative roles in pathogen detection, activation of immunity signal transduction pathways, and defense; as well as non-immunity activities [6]. Part of the non-immunity related genes we identified twenty SMGs that encode proteins required for the wild-type function of thorax skeletal muscle tissue, including Actin 88F (Act88F), Tropomyocin 2 (Tm2), held up (hdp), and Glutathione S transferase 2 (Gst2) were up-regulated 1 h post-injury relative to naïve flies (Fig. 1A). SMG up-regulation was greater in response to CF5 than PA14, especially during early (1–12 h) infection [Fig. 1B, C and Supplementary Information (SI) Table S1]. For instance, Act88F is induced 10.8-fold by CF5 and only 4.7-fold by PA14 inoculation, almost equal to the response to injury alone (Fig. 1A–C). This difference in gene expression was confirmed by the act88F-lacZ reporter gene [SI Fig. S1]. Such a difference in expression could be due to PA14 triggering less SMG up-regulation than CF5. Alternatively, PA14 could suppress a host pathway that signals SMG induction in response to injury and infection. SMG up-regulation at 1 h post-inoculation was lower in response to PA14 plus CF5 than CF5 alone, and similar to that triggered solely by PA14 (Fig. 1D). This suppression is likely not due to apoptosis, as PA14 does not cause noticeable apoptotic gene expression within the first 12 h of infection [6]. Also the differential SMG response is not due to growth disparity, as these strains proliferate equally in the fly thorax through 12 h post-inoculation [6]. These results suggest that PA14 actively restricts SMG induction.


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)

Highly virulent P. aeruginosa actively restricts skeletal muscle gene induction within 1 h post-inoculation.Relative expression ratio levels of 20 fly genes that encode proteins with essential functions of thorax skeletal muscle, under different conditions: 1, 6, and 12 h after thoracic injury only (A), thoracic injury and PA14 inoculation (B), or thoracic injury and CF5 inoculation (C); 1 h following thoracic injury and co-infection with 100∶100 and 200∶100 PA14:CF5 CFUs/fly (D); or following abdominal injury alone or together with inoculation with PA14 or CF5 (E). The relative expression ratio levels of selected SMGs for each condition were calculated versus naïve. The statistical evaluation of differences in expression values between PA14 and CF5 inoculated flies is presented in Table S1.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2131783&req=5

pone-0001356-g001: Highly virulent P. aeruginosa actively restricts skeletal muscle gene induction within 1 h post-inoculation.Relative expression ratio levels of 20 fly genes that encode proteins with essential functions of thorax skeletal muscle, under different conditions: 1, 6, and 12 h after thoracic injury only (A), thoracic injury and PA14 inoculation (B), or thoracic injury and CF5 inoculation (C); 1 h following thoracic injury and co-infection with 100∶100 and 200∶100 PA14:CF5 CFUs/fly (D); or following abdominal injury alone or together with inoculation with PA14 or CF5 (E). The relative expression ratio levels of selected SMGs for each condition were calculated versus naïve. The statistical evaluation of differences in expression values between PA14 and CF5 inoculated flies is presented in Table S1.
Mentions: In a previous study we profiled and compared the host responses that underlie susceptible versus non-susceptible D. melanogaster-P. aeruginosa interactions using PA14 and CF5 [6], two human P. aeruginosa isolates that are highly virulent and non-virulent in flies, respectively [8]. Our results showed that the fly whole genome expression responses to thorax infection by these two strains were strikingly different. We identified pathogenesis- and defense-specific genes with putative roles in pathogen detection, activation of immunity signal transduction pathways, and defense; as well as non-immunity activities [6]. Part of the non-immunity related genes we identified twenty SMGs that encode proteins required for the wild-type function of thorax skeletal muscle tissue, including Actin 88F (Act88F), Tropomyocin 2 (Tm2), held up (hdp), and Glutathione S transferase 2 (Gst2) were up-regulated 1 h post-injury relative to naïve flies (Fig. 1A). SMG up-regulation was greater in response to CF5 than PA14, especially during early (1–12 h) infection [Fig. 1B, C and Supplementary Information (SI) Table S1]. For instance, Act88F is induced 10.8-fold by CF5 and only 4.7-fold by PA14 inoculation, almost equal to the response to injury alone (Fig. 1A–C). This difference in gene expression was confirmed by the act88F-lacZ reporter gene [SI Fig. S1]. Such a difference in expression could be due to PA14 triggering less SMG up-regulation than CF5. Alternatively, PA14 could suppress a host pathway that signals SMG induction in response to injury and infection. SMG up-regulation at 1 h post-inoculation was lower in response to PA14 plus CF5 than CF5 alone, and similar to that triggered solely by PA14 (Fig. 1D). This suppression is likely not due to apoptosis, as PA14 does not cause noticeable apoptotic gene expression within the first 12 h of infection [6]. Also the differential SMG response is not due to growth disparity, as these strains proliferate equally in the fly thorax through 12 h post-inoculation [6]. These results suggest that PA14 actively restricts SMG induction.

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