1634. Blockade of Ccr1 is an immune-based approach that protects mice from systemic candidiasis of hematogenous origin
Session: Poster Abstract Session: Mycology - There's a Fungus Among Us: Treatment
Friday, October 28, 2016
Room: Poster Hall
Background: Systemic candidiasis is a leading cause of nosocomial bloodstream infection in the US. Vaccines are not available, and despite antifungal therapy, mortality of infected patients exceeds 40%. Therefore, novel immune-based strategies are highly desirable to augment or supplement the current antifungal drug treatment against candidiasis and improve patient outcomes. We have previously shown that genetic deficiency of the chemokine receptor Ccr1 in mice results in ameliorated renal tissue injury and improved survival after systemic candidiasis (Lionakis et al., PLoS Pathog, 2012). BL5923 is a specific Ccr1 antagonist, which has been shown to protect mice from diabetic nephropathy, lupus nephritis and colon cancer liver metastasis.

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.

Michail Lionakis, MD, ScD, Fungal Pathogenesis Unit, Laboratory of Clinical Infectious Diseases, Niaid, National Institute of Allergy and Infectious Diseases (NIAID), Bethesda, MD, Nathaniel Albert, BS, MD Anderson Cancer Center, Houston, TX, Muthulekha Swamydas, PhD, Fungal Pathogenesis Unit, Laboratory of Clinical Infectious Diseases, Niaid, National Institutes of Health, Bethesda, MD, Pius Loetscher, PhD, Autoimmunity, Transplantation and Inflammation, Novartis Institutes for BioMedical Research (NIBR), Basel, Switzerland and Dimitrios P. Kontoyiannis, MD, ScD, FIDSA, Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX

Disclosures:

M. Lionakis, None

N. Albert, None

M. Swamydas, None

P. Loetscher, Novartis: Employee , Salary

D. P. Kontoyiannis, •: 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

Findings in the abstracts are embargoed until 12:01 a.m. CDT, Wednesday Oct. 26th with the exception of research findings presented at the IDWeek press conferences.