Delayed Therapy with Plasma Gelsolin Improves Survival in Murine Pneumococcal Pneumonia

Abstract

Abstract Background: Innate immune responses contribute to successful resolution of bacterial pneumonia. Bolstering host defense with immunomodulators might be increasingly needed to improve outcomes in antibiotic-resistant infections. One candidate molecule is recombinant human plasma gelsolin (rhu-pGSN), an abundant normal blood protein whose levels fall proportionally with disease severity. Pretreatment with rhu-pGSN has beneficial effects in many pre-clinical models of inflammation and injury, including pneumonia. We evaluated the effects of delaying therapy with rhu-pGSN up to 48 hours after lethal intra-nasal pneumococcal challenge in a mouse model to more closely mimic realistic clinical circumstances. Methods: Adult Bl/6 mice were inoculated intra-nasally with S. pneumoniae serotype 3 on day 0, followed by subcutaneous rhu-pGSN 24 hours later for evaluation of bacterial clearance in lavage fluids. To assess effects on survival, rhu-pGSN was administered on days 2 and 3 after infection and effects monitored for 10 days. No antibiotics or other interventions were given. Results: Treatment with rhu-pGSN at 24 hours after infection improved bacterial clearance, seen as reduction of bacterial CFU in bronchoalveolar lavage fluid at 48 hours (% of initial inoculum, vehicle vs.. rhu-pGSN (dose range 0.5–2 mg): 30 ± 13 vs. 11 ± 7, n = 6 trials using inocula ranging 0.3–1.8 x 106 CFU, 3 mice/group/trial, P = .001). In 3 separate trials, pGSN (0.5 mg s.c.) reduced weight loss and mortality (% survival, vehicle vs. pGSN: 40 vs. 80, 0 vs. 25, 17 vs. 43; n ≥ 16/group, P =.02). Increasing the dose to 1 mg further improved survival from 17 to 71%. Conclusion: Rhu-pGSN can substantially improve survival in a murine model of fatal pneumococcal pneumonia, even when administered as single doses on days 2 and 3 after infection without antibiotics. The data support further evaluation of pGSN as adjunctive therapy for serious infections with diverse pathogens and in models of antibiotic-resistant pneumonia. Disclosures Z. Yang, BioAegis: Shared NIH grant to study plasma gelsolin, we receive plasma gelsolin for our lab studies; S. Levinson, BioAegis: BIoAegis shares a grant to investigate plasma gelsolin with HSPH, Employee and Shareholder, Salary; T. Stossel, BioAegis: Consultant and Shareholder, portion of royalties from Hospital IP licensed to BioAegis; M. DiNubile, BioAegis: Employee and Shareholder, Consulting fee; L. Kobzik, BioAegis: Collaborator and We share a NIH grant on pGSN with BioAegis, we receive plasma gelsolin for our lab studies