title: The effect of trauma on invasive group A streptococcal disease.
abstract: BACKGROUND
  Necrotising fasciitis due to invasive group A streptococcus (iGAS) is frequently associated with type emm1 isolates, with an attendant mortality of 40%. Some cases occur in previously healthy individuals with a history of upper respiratory tract infection, soft tissue contusion, and no obvious portal of entry. Using a new model of mild contusion injury, we set out to determine the effect of contusion on iGAS bacterial burden, phenotype, and host cytokine response.
  
  
  METHODS
  A new model of mild contusion was developed using a weight drop device and characterised in two strains of mice, CD1 and FVB/n. The effect of contusion on emm1 iGAS infection was assessed in three murine models of infection: lower respiratory tract (intranasal challenge of 1 × 10(7) colony forming units [CFU] per mouse), intravenous (1 × 10(7)· per mouse via the lateral tail vein), and muscle (1 × 10(8) CFU per mouse intramuscularly) at three timepoints after injury (24, 48, and 72 h). Bacterial burden, host cytokine response, and histological changes were analysed. Further molecular work was performed to assess the change in bacterial morphology observed after contusion injury in the muscle model. Mann-Whitney U test was used to compare differences in bacterial burden and cytokine responses between trauma and control groups.
  
  
  RESULTS
  Application of a force of 15·7 mJ resulted in histological changes in muscle consistent with mild trauma with no evidence of overlying skin injury, no bony injury, and minimum cytokine response. Contusion to soft tissue had no effect on bacterial burden or cytokine response in a mouse model of systemic infection (after intravenous inoculation) at three timepoints. Despite bacteraemia, specific seeding of the contused tissue did not occur in this model. By contrast, blunt contusion affected progression of a subsequent local GAS muscle infection and increased dissemination to blood in the lower respiratory tract infection model. Specifically, contusion increased emm1 GAS dissemination locally to draining lymph nodes (controls median 183 CFU per node [IQR 8-5800] vs trauma group 20 000 [1875-601 250]). Dissemination to lymph node was linked to a phenotypic change in bacterial capsule morphology. This phenotypic change was stable despite passage, consistent with a genetic change, and was associated with an increase in bacterial hyaluronan production (mucoid colonies 200 μg per CFU and no detectable capsule production in the non-mucoid colonies).
  
  
  CONCLUSIONS
  We found that non-penetrating trauma was associated with an enhanced susceptibility to invasive GAS disease. This model of mild contusion did not provide a focus for initiation or seeding of bacteraemic infection but instead provided an environment that determined the phenotype of the bacteria and enhanced local dissemination after iGAS infection at the same site. The environmental and genetic cues underlying dissemination are the subject of continuing research.
  
  
  BACKGROUND
  Royal Army Medical Corps, Surgeon General's Research Strategy Group, Ministry of Defence.
authors: Imperial College London, London, UK. Electronic address: DrLucyLamb@gmail.com.
authors: Lucy
authors: L
authors: Lamb
authors: Imperial College London, London, UK.
authors: Warren
authors: W
authors: McDonald
authors: Mary Lyon Centre, MRC Harwell, Didcot, UK.
authors: Cheryl
authors: C
authors: Scudamore
authors: Imperial College London, London, UK.
authors: Lionel
authors: L
authors: Tan
authors: Imperial College London, London, UK.
authors: Nicola
authors: N
authors: Lynskey
authors: Imperial College London, London, UK.
authors: Shiranee
authors: S
authors: Sriskandan