Passive immunization with CotH3 antibodies protects neutropenic mice from lethal mucormycosis through enhancing macrophage killing (MPF6P.660)

Abstract

Abstract Mucormycosis is a fatal fungal infection caused commonly by Rhizopus. We recently identified R. oryzae CotH3 as a surface protein which mediates invasion of host cells. CotH3 is present in other fungi that cause mucormycosis. Previously, we found polyclonal anti-CotH3 antibodies (CotH3-Abs) to block host cell invasion by R. oryzae and protect diabetic ketoacidotic mice from mucormycosis. Because neutropenic patients are also predisposed to mucormycosis, we used a cyclophosphamide/cortisone acetate injected mice to detect if CotH3-Abs protect against mucormycosis. Mice were infected intratracheally with R. oryzae, Mucor, Lichtheimia, Apophysomyces, Rhizomucor, or Cunninghamella prior to treating with CotH3-Abs (0.3mg, 0.1mg or 0.03mg) at different times post infection (4, 16, or 48h). All treatment doses showed enhanced survival of mice infected with R. oryzae vs. placebo-treated mice when used 16h post infection (p<0.005). The 0.03mg dose given 16h post infection demonstrated better survival outcome vs. higher doses. Protection was time dependent with higher survival of mice receiving CotH3-Abs at earlier time points post infection. Further, CotH-Abs prolonged survival of mice infected with each of the other tested organisms. Finally, CotH3-Abs reduced tissue fungal burden in target organs and dramatically enhanced mouse macrophage killing via enhancing lysosomal synthesis. Our studies warrant further development of CotH3-Abs as a novel therapy for mucormycosis.