A Novel Two-Hit Murine Model of Viral Primed Sepsis-Associated Acute Kidney Injury

Viral priming refers to the host's recognition of viral components, triggering an antiviral response and upregulating pathogen recognition receptors. When followed closely by bacterial infection, this immune activation can provoke a hyperinflammatory response, increasing the risk for secondary hemophagocytic lymphohistiocytosis (sHLH), multiorgan failure, and death. We developed a novel murine two-hit model of viral-primed sepsis-associated acute kidney injury (SA-AKI) using polyinosinic-polycytidylic acid (poly(I:C)) for viral mimicry and lipopolysaccharide (LPS) for bacterial stimulation. Male 8-week-old C57BL/6J mice were primed with poly(I:C) (2.5 mg/kg, intraperitoneal (IP) injection) at 24 hours prior to low-dose LPS (0.5 mg/kg, IP) (time = 0 hours) and compared to vehicle-treated controls for up to 48 hours. Poly(I:C)+LPS mice exhibited a significant reduction in glomerular filtration rate at 4 hours post-LPS, and elevated serum creatinine and urinary kidney injury molecule-1 (KIM-1) at 48 hours, indicating sustained kidney injury. These mice also showed marked increases in plasma ferritin, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) at 8 hours post-LPS versus non-primed LPS-treated mice, consistent with a hyperinflammatory state. Poly(I:C) alone induced a rapid type I interferon response, with elevated plasma IFNα, IFNβ, and renal Ifnb1 expression by 4 hours post-injection. This model effectively replicates viral-bacterial co-infection and provides a valuable platform to dissect the mechanisms linking viral priming to dysregulated immune responses and acute tubular injury in sepsis.