Traumatic Brain Injury Enhances Susceptibility to Lung Bacterial Infection in Mice and Pigs by Modulating the Innate Immune Response.

Abstract

Traumatic brain injury (TBI) leads to immune dysregulation, which predisposes patients to infections. We hypothesized that TBI leads to poor lung bacterial clearance, due at least in part to dysfunctional neutrophil (PMN) responses. In this study, we characterized both murine and porcine models of TBI plus lung bacterial inoculation to evaluate the effects of TBI on bacterial clearance, and tested the effects of plasma harvested from human TBI patients on PMN function. C57BL6 mice or Yucatan mini swine underwent sham (anesthesia only) or a mild TBI using standardized methods. Four hours later, mice were inoculated with Staphylococcus aureus. Pigs were inoculated with Actinobacter pleuropneumoniae immediately after TBI. At prespecified timepoints after inoculation (24 hr for mice and 72 hr for pigs), animals were euthanized and bronchoalveolar lavage (BAL) and blood were collected, and lung was harvested for further analyses. Plasma from TBI patients was used to perform in vitro assessment of PMN function. C57BL6 mice, Yucatan mini swine, healthy volunteers, and TBI patients. None. In both animal models, TBI predisposed to poor pulmonary bacterial clearance despite significantly increased PMNs in BAL and blood. In vitro, treatment of PMNs with plasma or plasma-derived extracellular vesicles (EVs) from TBI patients led to increased nondirectional chemokinesis, less reactive oxygen species production, and decreased ability to phagocytose. TBI leads to decreased bacterial clearance in the lung in models of TBI + bacterial lung infection, despite increased PMN counts in lung and blood. This is secondary to inappropriate PMN function after TBI, which we demonstrated in vitro via multiple functional assays to be caused, in part, by systemic factors in the plasma, including EVs. Further studies are required to understand the link between TBI and PMN dysfunction that leads to increased susceptibility to bacterial lung infection.