Methods: We examined the effect of pharmacological blockade of Ccr1 on the outcome of systemic candidiasis in vivo. We infected immunocompetent C57Bl/6 mice by intravenous injection of ~125,000 CFU of C. albicans SC5314 and treated them twice daily with either 50 mg/Kg of BL5923 or vehicle (hydroxyethyl cellulose) by oral gavage, starting 6 hours after infection. We assessed mouse survival, kidney tissue fungal burden, kidney weight and renal histology by Hematoxylin and eosin (H&E) and Periodic acid–Schiff (PAS) stains.
Results: Candida-infected mice treated with BL5923 had significantly improved survival at 2 weeks post-infection (50%) compared to vehicle-treated mice (10%; P = 0.0145) and had longer median survival of 10 days relative to 3 days in vehicle-treated mice. BL5923 treatment led to significantly decreased kidney tissue fungal growth (P = 0.018) and less pronounced injury-induced increase in kidney weight post-infection (P= 0.004). Histopathological analysis revealed that BL5923-treated mice sustained significantly less extensive kidney tissue damage with smaller areas of abscess formation and renal necrosis compared to vehicle-treated mice.
Conclusion: Treatment with a specific inhibitor of the chemokine receptor Ccr1 improves survival and ameliorates renal tissue injury during hematogenous candidiasis in non-neutropenic mice. These preclinical data suggest that adjunct pharmacological blockade Ccr1 represents a promising novel therapeutic intervention in systemic candidiasis that deserves further investigation.
M. Swamydas, None
P. Loetscher, Novartis: Employee , Salary
D. P. Kontoyiannis, â¢: Advisory Board , Research support
Pfizer: Research grant , Research support
Gilead: Invited lecturer , Speaker honorarium
Astellas: Consultant , Research support and Speaker honorarium
F2G: Consultant , Consulting fee
T2 Biosystems: Invited lecturer , Speaker honorarium
Mylan Inc: Invited lecturer , Speaker honorarium