Abstract
Severe trauma renders patients susceptible to infection. In sepsis, defective bacterial clearance has been linked to specific deviations in the innate immune response. We hypothesized that innate immune modulations observed during sepsis also contribute to increased bacterial susceptibility after severe trauma. A well-established murine model of burn injury, used to replicate infection following trauma, showed that wound inoculation with P. aeruginosa quickly spreads systemically. The systemic IL-10/IL-12 axis was skewed after burn injury with infection as indicated by a significant elevation in serum IL-10 and polarization of neutrophils into an anti-inflammatory (“N2”; IL-10+ IL-12−) phenotype. Infection with an attenuated P. aeruginosa strain (ΔCyaB) was cleared better than the wildtype strain and was associated with an increased pro-inflammatory neutrophil (“N1”; IL-10−IL-12+) response in burn mice. This suggests that neutrophil polarization influences bacterial clearance after burn injury. Administration of a TLR5 agonist, flagellin, after burn injury restored the neutrophil response towards a N1 phenotype resulting in an increased clearance of wildtype P. aeruginosa after wound inoculation. This study details specific alterations in innate cell populations after burn injury that contribute to increased susceptibility to bacterial infection. In addition, for the first time, it identifies neutrophil polarization as a therapeutic target for the reversal of bacterial susceptibility after injury.
Highlights
Each year traumatic injury accounts for over 40 million emergency room visits and 2 million hospital admissions across the United States [1]
Severe trauma results in a period of immune impairment that predisposes the patient to infectious complications, such as sepsis
The specific mechanisms that contribute to diminished bacterial clearance are not clearly defined
Summary
Each year traumatic injury accounts for over 40 million emergency room visits and 2 million hospital admissions across the United States [1]. Severe trauma predisposes patients to infection with rates as high as 37% of patients [2] Infectious complications, such as sepsis and pneumonia, increase the length of hospitalization and cost of treatment [3,4]. It is clear that severe burn-injury results in a complex interaction of both innate and adaptive immunity that leads to immune dysfunction, infection and often sepsis. TLR signaling leads to the induction or suppression of hundreds of inflammatory genes that further influence an immune response [21,22]. These innate immune responses lead to clearance of invading bacteria
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