Impaired host defense in mice deficient in myeloperoxidase

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Myeloperoxidase (MPO) is located within neutrophils capable of producing hypochlorous acid. Generation of oxidative products by phagocytic cells is known to be an important host defense mechanism directed toward killing of invading microorganisms. The importance of two major oxidant-producing enzymes, myeloperoxidase (MPO) and NADPH-oxidase, in in vivo fungicidal action was directly compared with genetically engineered mice. Although both MPO-deficient (MPO-KO) and NADPH-oxidase-deficient (CGD) mice showed increased susceptibility to pulmonary infections with Candida albicans and Aspergillus fumigatus compared with normal mice, superoxide (O_<2->) produced by NADPH-oxidase is more important than hypochlorous acid (HOCl) produced by MPO. We also observed that MPO-KO/CGD double knockout mice showed comparable levels of susceptibility to the CGD mice against C.albicans and A.fumigatus, indicating that MPO is unable to play a role in host defense in the absence of NADPH-oxidase. This strongly suggests that hydrogen peroxide, the precursor of HOCl, is solely derived from O_<2-> produced by NADPH-oxidase.To define the in vivo contribution of MPO to host defense against Cryptococcus infection, MPO-KO and control mice were infected with C.neoformans, and their survivals and fungal organ burdens were persued and the resulting data emphasize the essential role of MPO-dependent oxidative system for host defense against C.neoformans in vivo.