Delayed Therapy with Plasma Gelsolin Improves Survival in Murine Pneumococcal Pneumonia

Abstract

BackgroundInnate 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.MethodsAdult 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.ResultsTreatment 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%.ConclusionRhu-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