Graduate Student St. Jude Grad. Sch. of Biomed. Sci. Memphis, Tennessee, United States
Disclosure(s):
Ashton T. McKinnon, MS: No financial relationships to disclose
Introduction/Rationale: Respiratory syncytial virus (RSV) and Streptococcus pneumoniae (Spn) are leading causes of respiratory infections in children under the age of five. Nearly all infants are infected with RSV by age two, with 36% experiencing reinfection, while 65% of children are exposed to Spn. Despite this high prevalence, little is understood about the long-term impact a primary RSV infection impacts the susceptibility to subsequent bacterial exposure. Trained immunity, defined innate immunological memory driven by epigenetic modifications and metabolic reprogramming, can enhance the responsiveness of alveolar macrophages (AMs) to subsequent infections.
Methods: Mice are infected with RSV and monitored for weight loss and respiratory function over 10 days and then challenged with Spn and observed for 48 hours. Tissues are collected for CFU counts, ELISA, and flow cytometry. Pharmacological inhibitors are used to identify immune mechanisms driving RSV-mediated protection against Spn.
Results: Preliminary data reveals that AMs previously exposed to RSV are transcriptionally distinct from naïve AMs. Prior RSV infection induces protection against a subsequent challenge with Spn, demonstrated by enhanced recovery in weight loss and airway obstruction in mice previously infected with RSV compared to naïve mice, along with a 2-3-log reduction in bacterial burden in the lungs, nasal passages, and blood up to 30 days post-viral infection. Prior RSV infection results in heightened AM expression of CD80, CD86, MHC II, and LAMP-1, indicating enhanced function. Importantly, blocking IL-1β during RSV infection abrogates this protection, highlighting a critical role for IL-1 signaling.
Conclusion: Our results suggest that IL-1β production during RSV infection induces protection against Spn following viral clearance through non-specific trained immunity of AMs. This work highlights a novel mechanism of cross-protection in respiratory infection with potential implications for therapeutic strategies targeting innate immune memory.
