Here we identified and demonstrated that a set of SMGs constitutes host genetic components that contribute to the local hyper-susceptibility to P. aeruginosa infection in injured tissue, providing novel insights into the pathophysiology of trauma and the relationship between injury and infection. Our results showed that highly virulent P. aeruginosa cells actively impeded upregulation of protective SMG responses at the site of injury, while non-virulent P. aeruginosa cells promoted SMG upregulation. Furthermore, we found that SMG activation was tightly controlled by the JNK kinase Hep, whose activation at the injury site restricted bacterial growth and delayed mortality, linking JNK signaling to the hyper-susceptibility to infection in trauma. Functional expression studies that assess the role of specific SMGs in restricting infection at the site of injury, demonstrated that wild-type expression of the skeletal muscle structural genes TroponinC41C and Gst2 play an early role in restricting infection at the injury site.
Local and systemic SMG responses could be distinguished in our experimental model. SMG expression is induced by thoracic injury alone, a fact consistent with SMG involvement in tissue repair. However, SMG expression is prolonged when bacteria are present in the injury, with bacterially-mediated up-regulation being significantly higher in response to non-virulent CF5 versus virulent PA14 cells, especially during early infection. Although PA14 infection produces additional tissue damage, and presumably a greater need for muscle restoration, SMG expression was not, or only slightly, upregulated beyond that seen with injury. Hence PA14 cells should have access to nutrients released in the microenvironment of the wounded muscle, promoting more aggressive proliferation. Indeed, we showed that thoracic injury and PA14 inoculation promotes high CFU titers locally, and have observed muscle fiber disruption
within 24 h of thoracic injury and infection. Such damage is absent in CF5 inoculated flies (data not shown).
As in flies, involvement of muscle tissue in response to external injury is commonly observed in mammals. Following skin damage, underlying muscle may provide a physical barrier to pathogen invasion. In this regard, SMG expression could counteract muscle tissue decay by replenishing muscle structure components. Another aspect of muscle “resistance” to bacterial proliferation could be its detoxification properties. Muscle gene expression includes the upregulation of Gst2
, a gene with detoxification properties 
. By scavenging lipid peroxidation radicals 
, Gst2 can potentially increase the tolerance of infected tissue to cytotoxicity and cell death. Therefore, muscle structure support mediated by structural component restoration and possible tissue detoxification via Gst2 could act in concert to keep muscle destruction in check and limit bacterial proliferation during infection ().
The induction of SMG expression in response to infection is coupled to antimicrobial peptide gene expression through a common upstream signaling pathway 
. Our work shows that SMG induction acts as a homeostatic mechanism to support host defenses. This response can be a complementary defense mechanism to the increased systemic antimicrobial peptide production following injury and infection. Similarly, findings of a functional genomics analysis of mosquito responses to parasite invasion, suggested that cytoskeletal gene induction of the local epithelia constitute, together with the systemic humoral immunity, an integrated defense against infection 
. Notably, the JNK-dependent SMG-mediated “defense” response against P. aeruginosa
relies on small differences in gene expression levels. We propose that it is the collective response of many muscle genes that orchestrates muscle tissue restoration. Moreover, because the number of muscle cells injured and infected at the early time points are presumably a small percentage of the total, the expression profile of the whole fly reflects an underestimation of gene expression in the immediately affected muscle cells. Furthermore, small differences in gene expression can determine risk for specific human diseases 
. Since the JNK signaling cascade is important for multiple-defense related loci, the JNK-pathway network may also include clinically significant muscle gene loci. Downregulation of SMG expression in hep1
flies could indicate a general role for the JNK pathway in muscle cytoskeleton homeostasis, similar to the role of JNK in neuronal cytoskeleton maintenance 
Our results also showed that JNK-mediated responses also function in mammals to restrict P. aeruginosa infections. Accordingly, local pharmacological potentiation of this pathway could provide a novel anti-infective approach to prevent deleterious P. aeruginosa wound infections that can lead to systemic sepsis in mammals. The development of approaches that modulate the JNK host response or interfere with its pathogen suppression could provide new treatments to limit infections in susceptible patients.