Modelling lung infection with Klebsiella pneumoniae after murine traumatic brain injury.

Pneumonia is a common comorbidity in patients with severe traumatic brain injury (TBI), and is associated with increased morbidity and mortality. In this study, we established a model of intratracheal Klebsiella pneumoniae administration in young adult male and female mice, at 4 days following an experimental TBI, to investigate how K. pneumoniae infection influences acute post-TBI outcomes. A dose-response curve determined the optimal dose of K. pneumoniae for inoculation (1 x 10^6 colony forming units), and administration at 4 days post-TBI resulted in transient body weight loss and sickness behaviors (hypoactivity and acute dyspnea). K. pneumoniae infection led to an increase in pro-inflammatory cytokines in serum and bronchoalveolar lavage fluid at 24 h post-infection, in both TBI and sham (uninjured) mice. By 7 days, when myeloperoxidase + neutrophil numbers had returned to baseline in all groups, lung histopathology was observed with an increase in airspace size in TBI + K. pneumoniae mice compared to TBI + vehicle mice. In the brain, increased neuroinflammatory gene expression was observed acutely in response to TBI, with an exacerbated increase in Ccl2 and Hmox1 in TBI + K. pneumoniae mice compared to either TBI or K. pneumoniae alone. However, the presence of neuroinflammatory immune cells in the injured brain, and the extent of damage to cortical and hippocampal brain tissue, was comparable between K. pneumoniae and vehicle-treated mice by 7 days. Examination of the fecal microbiome across a time course did not reveal any pronounced effects of either injury or K. pneumoniae on bacterial diversity or abundance. Together, these findings demonstrate that K. pneumoniae lung infection after TBI induces an acute and transient inflammatory response, primarily localized to the lungs with some systemic effects. However, this infection had minimal impact on secondary injury processes in the brain following TBI. Future studies are needed to evaluate the potential longer-term consequences of this dual-hit insult.

Experimental Models of Hospital-Acquired Infections After Traumatic Brain Injury: Challenges and Opportunities.

Patients hospitalized after a moderate or severe traumatic brain injury (TBI) are at increased risk of nosocomial infections, including bacterial pneumonia and other upper respiratory tract infections. Infections represent a secondary immune challenge for vulnerable TBI patients that can lead to increased morbidity and poorer long-term prognosis. This review first describes the clinical significance of infections after TBI, delving into the known mechanisms by which a TBI can alter systemic immunological responses towards an immunosuppressive state, leading to promotion of increased vulnerability to infections. Pulmonary dysfunction resulting from respiratory tract infections is considered in the context of neurotrauma, including the bidirectional relationship between the brain and lungs. Turning to pre-clinical modeling, current laboratory approaches to study experimental TBI and lung infections are reviewed, to highlight findings from the limited key studies to date that have incorporated both insults. Then, practical decisions for the experimental design of animal studies of post-injury infections are discussed. Variables associated with the host animal, the infectious agent (e.g., species, strain, dose, and administration route), as well as the timing of the infection relative to the injury model are important considerations for model development. Together, the purpose of this review is to highlight the significant clinical need for increased pre-clinical research into the two-hit insult of a hospital-acquired infection after TBI to encourage further scientific enquiry in the field.