Persistent Neuroinflammation and Brain-Specific Immune Priming in a Novel Survival Model of Murine Pneumosepsis

Abstract

Pneumonia is the leading cause of sepsis and septic shock. Patients who survive pneumonia are vulnerable to long-term complications including increased risk of neurocognitive dysfunction. This study investigated the immune response and long-term complications of a non-surgical mouse model of Klebsiella pneumoniae pneumosepsis with antibiotic treatment. Pneumosepsis resulted in acutely enhanced expression of inflammatory cytokines, chemokines, and damage-associated molecular patterns in the brain and spleen. Despite resolution of infection, murine pneumosepsis survivors demonstrated a deficit in exploratory locomotor behavior at 2 weeks. This was associated with brain-specific persistent inflammatory gene expression and infiltrating myeloid cells in the brain. The brain inflammatory response was also primed in response to secondary challenge with lipopolysaccharide. The findings of this study demonstrate behavioral and inflammatory outcomes that parallel observations in other models of sepsis, but that have not previously been described in antibiotic-treated pneumonia models, highlighting a common pathway to the development of chronic brain dysfunction in sepsis survival.

Long-term survivors of murine sepsis are predisposed to enhanced LPS-induced lung injury and proinflammatory immune reprogramming

“…This population exists in the lung at baseline and as has been previously observed to be expanded for weeks after sterile inflammation and sepsis due to CLP in mice (30,66,(68)(69)(70)(71). We and others have also previously observed persistent monocyte margination in the brain perivasculature days to weeks after experimental sepsis (27,36,72,73). This is the first report associating sterile lung injury many weeks after CLP with the presence of lung accumulating monocytes.…”

“…Several immune programs have been defined following acute infection, including tolerance (also immunoparalysis), priming, and trained immunity (12). Tolerance/ immunoparalysis is defined as the inability of immune cells to activate gene transcription upon secondary stimulation, leading to a reduced/hyporesponsive functional state (12)(13)(14). In contrast, both priming and trained immunity result in enhanced or synergistic responses to secondary stimuli, leading to an enhanced functional state; however, the latter is more specifically defined by lasting epigenetic alterations that drive this functional change (12).…”

Physiologic Effects of Exogenous Dextrose in Murine Klebsiella pneumoniae Sepsis Vary by Route of Provision

“…Pneumonia is the most common cause of sepsis but is not often utilized in murine septic models [ 24 ]. We developed a preclinical model of sepsis using oropharyngeal Klebsiella pneumoniae because (a) Klebsiella infection is common in septic patients, (b) the lung is a common route of entry for pathogens in clinical sepsis, (c) Klebsiella pneumoniae readily disseminates after initial pulmonary infection, and (d) systemic inflammation and decompensation develop approximately one day after the initial insult, thereby modeling the course of septic patients.…”

Cytokines in the Brain and Neuroinflammation: We Didn’t Starve the Fire!

“…Moreover, both the peripheral administration of bacterial LPS and experimental sepsis models result in morphological signs of microglial activation [98][99][100]. Furthermore, both procedures induce immune cell infiltration of the brain [101][102][103][104][105][106]. Finally, regarding cerebral tissue damage, both BBB breakdown and neuronal death have been studied.…”